Oxazalidinone compounds and methods of preparation and use thereof

ABSTRACT

Oxazolidinones and methods for their synthesis are provided. Further provided are methods of making biologically active oxazolidinones as well as pharmaceutically acceptable compositions comprising the oxazolidinones. Oxazolidinones as disclosed herein can be readily synthesized and used in a variety of applications including use as antimicrobial agents. In one embodiment, a variety of thioamidomethyloxazolidinones and methods for their synthesis and use are provided.

CROSS-REFERENCE TO RELATED APPLICATIONS

This is a division of U.S. patent application Ser. No. 09/625,756 filedJul. 26, 2000, now U.S. Pat. No. 6,441,005 which claims the benefitunder 35 U.S.C. §119(e) of U.S. provisional patent application SerialNo. 60/146,012, filed Jul. 28, 1999, the disclosures of which are herebyincorporated herein by reference.

FIELD OF THE INVENTION

The present invention is directed to oxazolidinones, oxazolidinonecompositions, and methods for their preparation and use.

BACKGROUND ART

Oxazolidinones are compounds where an amine group and a hydroxyl groupon adjacent carbon atoms have been cyclized to form a 5-membered ringcontaining a carbonyl group. Certain oxazolidinones have been shown toexhibit a variety of biological activities. For example, someoxazolidinones are inhibitors of monoamine oxidase-B, an enzymeimplicated in Parkinson's disease. See, for example, Ding et al., J.Med. Chem. 36:3606-3610 (1993).

Scientists have reported that certain oxazolidinone derivatives exhibitbeneficial antibacterial effects. For instance,N-[3-[3-fluoro-4-(morpholin-4-yl)phenyl]2-oxooxazolidin-5(s)-ylmethyl]acetamide(below) has been reported to be useful for the treatment of bacterialinfections. Lizondo et al., Drugs of the Future, 21:1116-1123 (1996).

A ten step synthesis of oxazolidinone antibiotics has been described.U.S. Pat. No. 5,547,950. A four step synthesis of the antibacterialcompound U-100592 also has been reported. Schauss et al., TetrahedronLetters, 37:7937-7940 (1996). A five step preparation ofenantiomerically pure cis- andtrans-N-(propionyl)hexahydrobenzoxazolidin-2-ones further was reported.De Parrodi et al., Tetrahedron: Asymmetry, 8:1075-1082 (1997).

The synthesis of the oxazolidinone antibacterial agent shown below hasbeen reported. Wang et al., Tetrahedron, 45:1323-1326 (1989). Thisoxazolidinone was made using a process that included the reaction of ananiline with glycidol to provide an amino alcohol, and thediethylcarbonate mediated cyclization of the amino alcohol to afford anoxazolidinone.

The synthesis of oxazolidinone antibacterial agents, including thecompound shown below has been reported. U.S. Pat. No. 4,705,799. Theprocess used to make the compound shown below included a metal mediatedreduction of a sulfonyl chloride to provide a sulfide.

The synthesis of oxazolidinone antibacterial agents, including thepyridyl compound shown below has been reported. U.S. Pat. No. 4,948,801.The process used included an organometallic mediated coupling of anorganotin compound and an aryl iodide.

Other reports of syntheses of oxazolidinone compounds are described inDE 196 01 264 A1, EP 0 789 026 A1, DE 196 04 223 A1, EP 0 738 726 A1,and PCT WO 98/54161.

The synthesis of oxazolidinone compounds also is described in U.S.patent application Ser. No. 09/012,535, filed Jan. 23, 1998, U.S. patentapplication Ser. No. 09/086,702, filed May 28, 1998, U.S. patentapplication Ser. No. 09/235,771, filed Jan. 22, 1999, andPCT/US99/01318, filed Jan. 22, 1999, the disclosures of which areincorporated herein by reference in their entirety.

SUMMARY OF INVENTION

Provided are oxazolidinones, compositions comprising oxazolidinones, aswell as methods of their synthesis and use. Also provided arecompositions for the treatment or prevention of an infectious disordercomprising an effective amount of any oxazolidinone compound disclosedherein and a pharmaceutically acceptable carrier. Methods are providedof treating or preventing an infectious disorder in a human or otheranimal subject, comprising administering to the subject an effectiveamount of any oxazolidinone compound disclosed herein.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 shows the structure of some exemplary thiocarbonyl oxazolidinonecompounds.

FIG. 2 shows another embodiment of structures of some exemplarythiocarbonyl oxazolidinone compounds.

FIG. 3 shows further embodiments of the structure of some exemplarythiocarbonyl oxazolidinone compounds.

FIG. 4 shows further embodiments of the structure of some exemplarythiocarbonyl oxazolidinone compounds.

FIG. 5 shows further embodiments of the structure of some exemplarythiocarbonyl oxazolidinone compounds.

FIG. 6 shows structures of some exemplary oxazolidinone compounds offormula 2.

DETAILED DESCRIPTION

Definitions

As used herein, the terms and phrases have the meanings and definitionsknown in the art. Some of the more commonly used phrases are describedin more detail below.

“Combinatorial library” or “array” is an intentionally createdcollection of differing molecules which can be prepared syntheticallyand screened for biological activity in a variety of different formats(e.g., libraries of soluble molecules, libraries of molecules bound to asolid support). Typically, combinatorial libraries contain between about6 and two million compounds. In one embodiment, combinatorial librariescontain between about 48 and 1 million compounds. For example,combinatorial libraries may contain between about 96 and 250,000compounds. In another embodiment, combinatorial libraries may containabout 40 to 100 compounds.

“Alkyl” refers to a cyclic, branched or straight chain chemical groupcontaining only carbon and hydrogen, such as methyl, pentyl, andadamantyl. Alkyl groups can either be unsubstituted or substituted withone or more substituents, e.g., halogen, alkoxy, acyloxy, amino,hydroxyl, mercapto, carboxy, benzyloxy, phenyl, and benzyl. Alkyl groupscan be saturated or unsaturated (e.g., containing —C═C— or —C≡C—subunits), at one or several positions. Typically, alkyl groups willcomprise about 1 to 12 carbon atoms, for example about 1 to 10, or about1 to 8 carbon atoms.

“Heteroalkyl” refers to a cyclic, branched or straight chain chemicalgroup containing carbon, hydrogen and at least one heteroatom. Theheteroatom will be typically nitrogen, oxygen or sulfur. Heteroalkylgroups can either be unsubstituted or substituted with one or moresubstituents, e.g., halogen, alkoxy, acyloxy, amino, hydroxyl, mercapto,carboxy, benzyloxy, phenyl, benzyl. Where the heteroalkyl group containsa nitrogen atom, the nitrogen atom can be primary, secondary, tertiary,quaternary or can be in various forms such as an amide or sulfonamide.Heteroalkyl groups can contain one or more unsaturated (e.g., —C═C— or—C≡C—) subunits. Typically, heteroalkyl groups will comprise 1 to 12atoms, for example 1 to 8, or 1 to 4 carbon atoms.

“Aryl” refers to a monovalent unsaturated aromatic carbocyclic grouphaving a single ring (e.g. phenyl), multiple rings (e.g. biphenyl), ormultiple condensed rings (e.g. naphthyl or anthryl). Aryl groups can beoptionally unsubstituted or substituted with amino, hydroxyl, alkyl,heteroalkyl, alkoxy, halo, mercapto and other substituents. Typically,the aryl group is a substituted single ring compound. For example, thearyl group is a substituted phenyl ring.

“Heteroaryl” refers to a monovalent unsaturated aromatic carbocyclicgroup having a single ring (e.g., pyridyl or furyl) or multiplecondensed rings (e.g., indolizinyl or benzothienyl) and having at leastone heteroatom within the ring. The heteroatom in the ring is preferablynitrogen, oxygen or sulfur. Heteroaryl groups can be optionallyunsubstituted or substituted with amino, hydroxyl, alkyl, heteroalkyl,alkoxy, halo, mercapto and other substituents. In one embodiment, theheteroaryl group is substituted.

“Electron withdrawing group” refers to a substituent that drawselectrons to itself more than a hydrogen atom would if it occupied thesame position in a molecule. This definition according to field effectis discussed in March, “Advanced Organic Chemistry,” 3d Edition, pp.16-17, Wiley-Interscience, New York. It should be contrasted with adefinition based on resonance effects. Examples of electron withdrawinggroups include —NR₂, —COOH, —OR, —SR, —F, —COR, —Cl, —SH, —NO₂, —Br,—NH₂, —SO₂R, —I, —OH, —CN, —C═CR₂, where R is alkyl, heteroalkyl, arylor heteroaryl.

“Chemical module” refers to a general class of molecules that can beincorporated into a combinatorial library at a discrete step in thelibrary synthesis. For example, thiols are chemical modules that can becoupled to a substrate, where the synthetic route employs a nucleophileto displace a solid support bound leaving group; isocyanates arechemical modules that can be coupled to a substrate, where the syntheticroute employs an electrophile to react with a solid support bound amine.Chemical modules can contain tens, hundreds or thousands of differentindividual members.

“Protecting group” refers to a chemical group that exhibits thefollowing characteristics: (1) reacts selectively with the desiredfunctionality in good yield to give a protected substrate that is stableto the projected reactions for which protection is desired; 2) isselectively removable from the protected substrate to yield the desiredfunctionality; and 3) is removable in good yield by reagents compatiblewith the other functional group(s) generated in such protectionreactions. Examples of protecting groups can be found in Greene et al.(1991) Protective Groups in Organic Synthesis, 2nd Ed. (John Wiley &Sons, Inc., New York).

“Biologically active oxazolidinone compounds” or “bioactiveoxazolidinone compounds” refers to an oxazolidinone compound thatexhibits biological activity. For instance, a biologically activeoxazolidinone can inhibit the interaction between an enzyme or receptorand its respective substrate(s) or endogenous ligand(s), or inhibit cellgrowth of a microorganism, by about at least 15% at a solutionconcentration of 10⁻³ molar or lower (i.e., it has inhibitory activity).For example, the biologically active oxazolidinone will inhibit suchprocesses at solution concentrations of about 10⁻⁴ M or lower, or 10⁻⁵ Mor lower, or, e.g., of about 10⁻⁶ M or lower.

Oxazolidinones

Provided are oxazolidinones, and compositions comprising oxazolidinones,as well as methods for their synthesis, for example, by solid phasesynthesis methods, and methods for their use. A variety ofoxazolidinones are provided that optionally have biological activity,such as antimicrobial activity.

In one embodiment, oxazolidinones 1 are provided:

wherein in one embodiment:

R₆ is thioacyl, aminocarbonyl, alkoxycarbonyl, aminothiocarbonyl,alkoxythiocarbonyl, alkylthio(carbonyl), or alkylthio(thiocarbonyl);

R₇ is aryl or heteroaryl;

R₈ is alkyl (e.g., C₁-C₇ alkyl), alkenyl (e.g.,C₁-C₇ alkenyl), alkynyl(e.g., C₁-C₇ alkynyl), NR, O, S, C(═O)NR, NRC(═O), C(═O), C(═O)O,OC(═O), OC(═O)NR, NRC(═O)O, C(═S)NR, NRC(═S), C(═S), C(═S)O, OC(═S),OC(═S)NR, NRC(═S)O, S(═O), SO₂, SO₂NR, NRSO₂, NRCONR′, NRC(═S)NR′, or(CH₂)_(n)O, wherein n=0-20, e.g., 0-6, and wherein R and R′ areindependently H, alkyl, heteroalkyl, aryl or heteroaryl; and

R₉ is hydrogen, OH, OR″, SR″, NR″R′″, alkyl, aryl, heteroalkyl, orheteroaryl, and wherein R′ and R′″ are independently H, alkyl,heteroalkyl, aryl or heteroaryl.

In one embodiment of the compounds of formula 1:

R₈ is NR, S, C(═O)NR, NRC(═O), C(═O)O, OC(═O), OC(═O)NR, C(═S)NR,NRC(═S), OC(═S)NR, NRC(═S)O, or NRC(═S)NR′, wherein R and R′ areindependently H, alkyl, heteroalkyl, aryl or heteroaryl; and

R₉ is hydrogen, OR″, SR″, NR″R′″, alkyl, aryl, or heteroaryl, whereineach R″ and R′″ are independently H, alkyl, aryl or heteroaryl.

In one embodiment of the compounds of formula 1, R₆ is a thioacyl group.Exemplary thioacyl groups include C(═S)CH₃, C(═S)CH₂CH₃, C(═S)H, andC(═S)cyclopropyl.

Examples of oxazolidinone compounds are provided in FIGS. 1-5. FIG. 6further provides examples of oxazolidinone compounds of formula 2.

In one embodiment of the compounds of formula 1, R₈ is not aryl,heteroaryl, morpholino, piperazino, thiomorpholino, indolino, orthiopyrano. In one preferred embodiment, R₇ and R₉ are not directlybonded.

Also provided are compounds of formula 3:

wherein in one embodiment:

R₇ is aryl or heteroaryl;

R₈ is alkyl (e.g., C₁-C₇ alkyl), alkenyl (e.g., C₁-C₇ alkenyl), alkynyl(e.g., as C₁-C₇ alkynyl), NR, O, S, C(═O)NR, NRC(═O), C(═O), C(═O)O,OC(═O), OC(═O)NR, NRC(═O)O, C(═S)NR, NRC(═S), C(═S), C(═S)O, OC(═S),OC(═S)NR, NRC(═S)O, S(═O), SO₂, SO₂NR, NRSO₂, NRCONR′, NRC(═S)NR′, or(CH₂)_(n)O, wherein n=0-20, e.g., 0-6, and wherein each R and R′ areindependently H, alkyl, heteroalkyl, aryl or heteroaryl;

R₉ is hydrogen, OH, OR″, SR″, NR″R′″, alkyl, aryl, heteroalkyl, orheteroaryl, and wherein each R″ and R′″ are independently H, alkyl,heteroalkyl, aryl or heteroaryl; and

R₁₀ is H, alkyl, heteroalkyl, aryl or heteroaryl.

In one embodiment of the compounds of formula 3, R₁₀ is H; alkyl such asC₁₋₄ alkyl; substituted alkyl such as C₁₋₄ alkyl substituted with 1-3 F,1-2 Cl, CN, NO₂ or COOC₁-C₄ alkyl; or R₁₀ is a C₃₋₆ cycloalkyl.

In one embodiment, R₁₀ is CH₃, CH₂CH₃, or cyclopropyl.

In another embodiment of the compounds of formula 3, R₈ is NR, S,C(═O)NR, NRC(═O), C(═O)O, OC(═O), OC(═O)NR, C(═S)NR, NRC(═S), OC(═S)NR,NRC(═S)O, or NRC(═S)NR′, wherein R and R′ are independently H, alkyl,heteroalkyl, aryl or heteroaryl; and

R₉ is hydrogen, OR″, SR″, NR″R′″, alkyl, aryl, or heteroaryl, wherein R″and R′″ are independently H, alkyl, aryl or heteroaryl.

There further is provided compounds of formula 4:

wherein:

R₇ is aryl or heteroaryl;

R₈ is NR, S, C(═O)NR, NRC(═O), C(═O)O, OC(═O), OC(═O)NR, C(═S)NR,NRC(═S), OC(═S)NR, NRC(═S)O, or NRC(═S)NR′, wherein R and R′ areindependently H, alkyl, heteroalkyl, aryl or heteroaryl; and

R₉ is hydrogen, OR″, SR″, NR″R′″, alkyl, aryl, or heteroaryl, wherein R″and R′″ each are independently H, alkyl, heteralkyl, aryl or heteroaryl;and

R₁₀ and R₁₁ are independently hydrogen, alkyl, heteroalkyl, aryl orheteroaryl, or NR₁₀R₁₁ is NH₂, NHC₁₋₄ alkyl, N(C₁-C₄alkyl)₂, orN(CH₂)₂₋₅.

There further are provided compounds of formula 5:

wherein, in one embodiment:

R₇ is aryl or heteroaryl;

R₈ is NR, S, C(═O)NR, NRC(═O), C(═O)O, OC(═O), OC(═O)NR, C(═S)NR,NRC(═S), OC(═S)NR, NRC(═S)O, or NRC(═S)NR′, wherein R and R′ areindependently H, alkyl, heteroalkyl, aryl or heteroaryl; and

R₉ is hydrogen, OR″, SR″, NR″R′″, alkyl, aryl, or heteroaryl, wherein R″and R′″ each are independently H, alkyl, heteroalkyl, aryl orheteroaryl; and

R₁₀ is alkyl, C₁-C₄ alkyl, heteroalkyl, aryl or heteroaryl.

Also provided are compounds of formula 6:

wherein in one embodiment:

R₇ is aryl or heteroaryl;

R₈ is alkyl (such as C₁-C₇ alkyl), alkenyl (such as C₁-C₇ alkenyl),alkynyl (such as C₁-C₇ alkynyl), NR, O, S, C(═O)NR, NRC(═O), C(═O),C(═O)O, OC(═O), OC(═O)NR, NRC(═O)O, C(═S)NR, NRC(═S), C(═S), C(═S)O,OC(═S), OC(═S)NR, NRC(═S)O, S(═O), SO₂, SO₂NR, NRSO₂, NRCONR′,NRC(═S)NR′, or (CH₂)_(n)O, wherein n=0-20, such as 0-6, and wherein Rand R′ are independently H, alkyl, heteroalkyl, aryl or heteroaryl;

R₉ is hydrogen, OH, OR″, SR″, NR″R′″, alkyl, aryl, heteroalkyl, orheteroaryl, and wherein R″ and R′″ are independently H, alkyl,heteroalkyl, aryl or heteroaryl;

R₁₀ and R₁₁ are independently hydrogen, alkyl, heteroalkyl, aryl orheteroaryl; or

NR₁₀R₁₁ is NH₂, NHC₁₋₄ alkyl, N(C₁-C₄alkyl)₂, or N(CH₂)₂₋₅.

In one embodiment, there are provided compounds of formula 6, wherein:

R₈ is NR, S, C(═O)NR, NRC(═O), C(═O)O, OC(═O), OC(═O)NR, C(═S)NR,NRC(═S), OC(═S)NR, NRC(═S)O, or NRC(═S)NR′, wherein R and R′ areindependently H, alkyl, heteroalkyl, aryl or heteroaryl; and

R₉ is hydrogen, OR″, SR″, NR″R′″, alkyl, aryl, or heteroaryl, wherein R″and R′″ are independently H, alkyl, aryl or heteroaryl.

Further provided are compounds of formula 7:

wherein in one embodiment:

R₇ is aryl or heteroaryl;

R₈ is alkyl (such as C₁-C₇ alkyl), alkenyl (such as C₁-C₇ alkenyl),alkynyl (such as C₁-C₇ alkynyl), NR, O, S, C(═O)NR, NRC(═O), C(═O),C(═O)O, OC(═O), OC(═O)NR, NRC(═O)O, C(═S)NR, NRC(═S), C(═S), C(═S)O,OC(═S), OC(═S)NR, NRC(═S)O, S(═O), SO₂, SO₂NR, NRSO₂, NRCONR′,NRC(═S)NR′, or (CH₂)_(n)O, wherein n=0-6, and wherein R and R′ areindependently H, alkyl, heteroalkyl, aryl or heteroaryl;

R₉ is hydrogen, OH, OR″, SR″, NR″R′″, alkyl, aryl, heteroalkyl, orheteroaryl, and wherein R″ and R′″ are independently H, alkyl,heteroalkyl, aryl or heteroaryl; and

R₁₀ is alkyl, heteroalkyl, aryl or heteroaryl.

In one embodiment of the compounds of formula 7:

R₈ is NR, S, C(═O)NR, NRC(═O), C(═O)O, OC(═O), OC(═O)NR, C(═S)NR,NRC(═S), OC(═S)NR, NRC(═S)O, or NRC(═S)NR′, wherein R and R′ areindependently H, alkyl, heteroalkyl, aryl or heteroaryl; and

R₉ is hydrogen, OR″, SR″, NR″R′″, alkyl, aryl, or heteroaryl, wherein R″and R′″ are independently H, alkyl, aryl or heteroaryl.

Also provided are compounds of the structure 1b:

wherein, in one embodiment:

R₂ and R₄ are, independently, hydrogen, alkyl, heteroalkyl, heteroarylor an electron withdrawing group;

R₆ is thioacyl, aminocarbonyl, alkoxycarbonyl, aminothiocarbonyl,alkoxythiocarbonyl, alkylthio(carbonyl), or alkylthio(thiocarbonyl); and

R₁ is:

C(O)NR₇R₈, C(S)NR₇R₈, OC(O)NR₇R₈, OC(S)NR₇R₈, NR₇C(O)N R₈R₉, NR₇C(S)NR₈R₉, wherein R₇, R₈, and R₉ are, independently, hydrogen, alkyl,heteroalkyl, aryl or heteroaryl;

C(O)OR₁₀, wherein R₁₀ is hydrogen, alkyl, heteroalkyl, aryl orheteroaryl;

C(O)R₁₁, wherein R₁₁ is hydrogen, alkyl, heteroalkyl, aryl orheteroaryl;

SR₁₂, S(O)₂R₁₂, or S(O)R₁₂, wherein R₁₂ is hydrogen, alkyl, heteroalkyl,aryl or heteroaryl;

NR₁₃R₁₄ wherein R₁₃ and R₁₄ are, independently, hydrogen, acyl,sulfonyl, alkyl, heteroalkyl, aryl or heteroaryl;

2-oxazolyl comprising R₁₅ at the 4-position and R₁₆ at the 5-position ofthe oxazolyl, wherein R₁₅ and R₁₆ are, independently, hydrogen, alkyl,heteroalkyl, aryl, heteroaryl or an electron withdrawing group;

2-aminothiazolyl comprising R₁₇ at the 4-position and R₁₈ at the5-position of the thiazole, wherein R₁₇ and R₁₈, are, independently,hydrogen, alkyl, heteroalkyl, aryl, heteroaryl or an electronwithdrawing group; and

CH₂NR₁₉R₂₀, wherein R₁₉ and R₂₀ are, independently, hydrogen, alkyl,heteroalkyl, aryl, heteroaryl, acyl or sulfonyl;

2-(1,3,4-thiadiazolyl) comprising R₂₁, at the 5-position of the1,3,4-thiadiazole, wherein R₂₁ is hydrogen, alkyl, heteroalkyl,amino(C₁₋₄ alkyl), acylamino(C₁₋₄ alkyl), thioacylamino(C₁₋₄-alkyl),sulfonamido(C₁₋₄alkyl), heterocarbonylamino(C₁₋₄ alkyl), aryl,heteroaryl, an electron withdrawing group, or NR₂₂R₂₃, wherein R₂₂ andR₂₃ are, independently, hydrogen, acyl, thioacyl, sulfonyl, alkyl,heteroalkyl, aryl or heteroaryl;

CH═CHR₂₄ or C≡CR₂₄, wherein R₂₄ is C(O)NR₇R₈, C(S)NR₇R₈, OC(O)NR₇R₈,OC(S)NR₇R₈, NR₇C(O)N R₈R₉, NR₇C(S)N R₈R₉, C(O)OR₁₀, C(O)R₁₁, SR₁₂,S(O)₂R₁₂, S(O)R₁₂, NR₁₃R₁₄, CH₂NR₁₉R₂₀, alkyl, aryl, or heteroaryl; or

5,6-dihydro-1,4,2-dioxazine-3-yl, wherein R₂₅ is at the 5-position ofdioxazine, and R₂₆ is at the 6-position of dioxazine, and wherein R₂₅and R₂₆, are, independently, hydrogen, alkyl, heteroalkyl, aryl,heteroaryl or an electron withdrawing group; and

wherein optionally R₁ and R₂ together are a quinolone heterocycleC(═O)C(COOH)═CHNR₂₇, or R₁ and R₂ together are a benzotriazoleheterocycle NNNR₂₇, or NN(R₂₇)N, wherein R₂₇ is alkyl, aryl, orheteroaryl.

Exemplary structures are shown below:

In one embodiment of the compounds of formula 1b: R₁ is C(O)NR₇R₈, SR₁₁,C(S)NR₇R₈, C(O)OR₁₀, C(O)R₁₁, SR₁₂, S(O)₂R₁₂, S(O)R₁₂ or NR₁₃R₁₄.

In another embodiment of the compounds of formula 1b: R₁ isNR_(x)(C═O)R_(y), wherein R_(x) and R_(y) are independently hydrogen,alkyl, heteroalkyl, aryl, or heteroaryl. In another embodiment, R₁ isNR_(x)(SO₂)R_(y), wherein R_(x) and R_(y) are independently hydrogen,alkyl, heteroalkyl, aryl, or heteroaryl with the proviso that R_(y) isnot H. In another embodiment, R₁ is 2-oxazolyl, wherein R₁₅ is at the4-position and R₁₆ is at the 5-position of the oxazole group. In afurther embodiment, R₁ is 2-aminothiazolyl, wherein R₁₇ is at the4-position and R₁₈ is at the 5-position of the aminothiazolyl group.

In one embodiment of the compounds of formula 1b, R₄ is hydrogen; R₂ isfluorine; R₆ is C(S)C₁₋₇ alkyl or C(S)C₃₋₆ cycloalkyl; R₁ is C(O)NR₇R₈and R₇ is hydrogen; and/or R₈ is heteroaryl. In another embodiment, R₄is hydrogen; R₂ is fluorine; and/or R₆ is C(S)CH₃, and NR₇R₈ isNH(5′-(5-aminopyridine-2-yl)thiopyridine-3′-yl) or NH(pyridine-3-yl) orNH(5-chloropyridine-3-yl).

Exemplary compounds of formula 1 are as follows. MIC refers to theminimal inhibitory concentration which was determined as described inExample 37.

In one embodiment, the compound shown below is provided, with, forexample, an MIC of 4-8 Tg/mL (S. aureus).

In another embodiment, the five compounds shown below are provided,with, for example, an MIC of 0.25 to 4 Tg/mL (S. aureus).

Other exemplary compounds include:

Exemplary compounds active against a fastidious Gram-negativemicroorganism H. influenzae are the following five compounds with an MICof 2-8 Tg/mL (H. influenzae):

Also provided are compounds of formula 3c:

wherein in one embodiment:

R₂ and R₄ are, independently, hydrogen, alkyl, heteroalkyl, heteroarylor an electron withdrawing group;

R₆ is thioacyl, aminocarbonyl, alkoxycarbonyl, aminothiocarbonyl,alkoxythiocarbonyl, alkylthio(carbonyl), or alkylthio(thiocarbonyl);

R₈ is alkyl (such as C₁-C₇ alkyl), alkenyl (such as C₁-C₇ alkenyl),alkynyl (such as C₁-C₇ alkynyl), NR, O, S, C(═O)NR, C(═S)NR, NRC(═O),NRC(═S), C(═O), C(═O)O, C(═S)O, OC(═O), OC(═S), S(═O), SO₂, SO₂NR,NRSO₂, NRCONR′, NRCSNR′, or (CH₂)_(n)O, wherein n=0-20, such as 0-6, andwherein R and R′ are independently H, alkyl, heteroalkyl, aryl orheteroaryl; and

R₉ is hydrogen, OH, OR″, SR″, NR″R′″, alkyl, aryl, heteroalkyl, orheteroaryl, and wherein R″ and R′″ are independently H, alkyl,heteroalkyl, aryl or heteroaryl.

In one embodiment of the compounds of formula 3c:

R₆ is C(S)C₁₋₇ alkyl or C(S)C₃₋₆ cycloalkyl;

R₇ is aryl;

R₈ is S; and

R₉ is alkyl or heteroalkyl.

In another embodiment of the compounds of formula 3c:

R₆ is C(S)C₁₋₇ alkyl or C(S)C₃₋₆ cycloalkyl;

R₇ is aryl;

R₈ is S(═O); and

R₉ is alkyl.

In another embodiment of the compounds of formula 3c:

R₆ is C(S)C₁₋₇ alkyl or C(S)C₃₋₆ cycloalkyl;

R₇ is aryl;

R₈ is OC(═O); and

R₉ is alkyl.

Examples of compounds of formula 3c include the following compound withMIC 4-8 Tg/mL (S. aureus).

Examples of compounds also include the following five compounds with MIC0.25-4 Tg/mL (S. aureus).

Also provided are compounds of formula 4c:

wherein in one embodiment:

R₆ is thioacyl, aminocarbonyl, alkoxycarbonyl, aminothiocarbonyl,alkoxythiocarbonyl, alkylthio(carbonyl), or alkylthio(thiocarbonyl);

Het₁ is heteroaryl;

R₈ is alkyl (such as C₁-C₇ alkyl), alkenyl (such as C₁-C₇ alkenyl),alkynyl (such as C₁-C₇ alkynyl), NR, O, S, C(═O)NR, C(═S)NR, NRC(═O),NRC(═S), C(═O), C(═O)O, C(═S)O, OC(═O), OC(═S), S(═O), SO₂, SO₂NR,NRSO₂, NRCONR′, NRCSNR′, or (CH₂)_(n)O, wherein n=0-20, e.g., 0-6, andwherein R and R′ are independently H, alkyl, heteroalkyl, aryl orheteroaryl; and

R₉ is hydrogen, OH, OR″, SR″, NR″R′″, alkyl, aryl, heteroalkyl, orheteroaryl, and wherein R″ and R′″ are independently H, alkyl,heteroalkyl, aryl or heteroaryl.

Also provided are compounds of formula 5c:

wherein:

R₂ and R₄ are, independently, hydrogen, alkyl, heteroalkyl, heteroarylor an electron withdrawing group;

R₆ is thioacyl, aminocarbonyl, alkoxycarbonyl, aminothiocarbonyl,alkoxythiocarbonyl, alkylthio(carbonyl), or alkylthio(thiocarbonyl);

R₈ is alkyl (such as C₁-C₇ alkyl), alkenyl (such as C₁-C₇ alkenyl),alkynyl (such as C₁-C₇ alkynyl), NR, O, S, C(═O)NR, C(═S)NR, NRC(═O),NRC(═S), C(═O), C(═O)O, C(═S)O, OC(═O), OC(═S), S(═O), SO₂, SO₂NR,NRSO₂, NRCONR′, NRCSNR′, or (CH₂)_(n)O, wherein n=0-20, e.g., 0-6, andwherein R and R′ are independently H, alkyl, heteroalkyl, aryl orheteroaryl; and

Het₂ is a heterocyclic group.

In one embodiment of the compounds of formula 5c:

R₆ is C(S)C₁₋₇ alkyl or C(S)C₃₋₆ cycloalkyl;

R₇ is aryl;

R₈is S; and

Het₂ is a thienylphenyl or thiazolyl group.

In another embodiment of the compounds of formula 5c:

R₆ is C(S)C₁₋₇ alkyl or C(S)C₃₋₆ cycloalkyl;

R₇ is aryl;

R₈ is NH; and

Het₂ is 1,3,5-triazinyl.

In one embodiment, the compound has the structure:

Other Oxazolidinone Compounds

In another embodiment, there are provided compounds of formula 8:

wherein:

R₇ is aryl or heteroaryl;

R₈ is C₁-C₇ alkyl, C₁-C₇ alkenyl, C₁-C₇ alkynyl, NR, O, S, C(═O)NR,NRC(═O), C(═O), C(═O)O, OC(═O), OC(═O)NR, NRC(═O)O, C(═S)NR, NRC(═S),C(═S), C(═S)O, OC(═S), OC(═S)NR, NRC(═S)O, S(═O), SO₂, SO₂NR, NRSO₂,NRCONR′, NRC(═S)NR′, or (CH₂)_(n)O, wherein n=0-6, and wherein R and R′are independently H, alkyl, heteroalkyl, aryl or heteroaryl;

R₉ is hydrogen, OH, OR″, SR″, NR″R′″, alkyl, aryl, heteroalkyl, orheteroaryl, and wherein R″ and R′″ are independently H, alkyl,heteroalkyl, aryl or heteroaryl;

R₁₀ and R₁₁ are independently hydrogen, alkyl, heteroalkyl, aryl,heteroaryl, acyl, thioacyl, CN, NO₂, alkoxycarbonyl, COOC₁₋₄ alkyl,sulfonyl, aminocarbonyl, aminothiocarbonyl, or alkoxythiocarbonyl; and

R₁₂ is hydrogen, alkyl, heteroalkyl, aryl, or heteroaryl.

Also provided are compounds of formula 9:

wherein:

R₇ is aryl or heteroaryl;

R₈ is C₁-C₇ alkyl, C₁-C₇ alkenyl, C₁-C₇ alkynyl, NR, O, S, C(═O)NR,NRC(═O), C(═O), C(═O)O, OC(═O), OC(═O)NR, NRC(═O)O, C(═S)NR, NRC(═S),C(═S), C(═S)O, OC(═S), OC(═S)NR, NRC(═S)O, S(═O), SO₂, SO₂NR, NRSO₂,NRCONR′, NRC(═S)NR′, or (CH₂)_(n)O, wherein n=0-6, and wherein R and R′are independently H, alkyl, heteroalkyl, aryl or heteroaryl;

R₉ is hydrogen, OH, OR″, SR″, NR″R′″, alkyl, aryl, heteroalkyl, orheteroaryl, and wherein R″ and R′″ are independently H, alkyl,heteroalkyl, aryl or heteroaryl; and

R₁₀ is alkyl, heteroalkyl, aryl, or heteroaryl, and n=0-2.

Further provided are compounds of formula 11:

wherein:

R₇ is aryl or heteroaryl;

R₈ is C₁-C₇ alkyl, C₁-C₇ alkenyl, C₁-C₇ alkynyl, NR, O, S, C(═O)NR,NRC(═O), C(═O), C(═O)O, OC(═O), OC(═O)NR, NRC(═O)O, C(═S)NR, NRC(═S),C(═S), C(═S)O, OC(═S), OC(═S)NR, NRC(═S)O, S(═O), SO₂, SO₂NR, NRSO₂,NRCONR′, NRC(═S)NR′, or (CH₂)_(n)O, wherein n=0-6, and wherein R and R′are independently H, alkyl, heteroalkyl, aryl or heteroaryl;

R₉ is hydrogen, OH, OR″, SR″, NR″R′″, alkyl, aryl, heteroalkyl, orheteroaryl, and wherein R″ and R′″ are independently H, alkyl,heteroalkyl, aryl or heteroaryl; and

R₁₀ is alkyl, C₁₋₄ alkyl, heteroalkyl, aryl or heteroaryl.

In another embodiment, there are provided compounds of formula 12:

wherein:

R₇ is aryl or heteroaryl;

R₈ is C₁-C₇ alkyl, C₁-C₇ alkenyl, C₁-C₇ alkynyl, NR, O, S, C(═O)NR,NRC(═O), C(═O), C(═O)O, OC(═O), OC(═O)NR, NRC(═O)O, C(═S)NR, NRC(═S),C(═S), C(═S)O, OC(═S), OC(═S)NR, NRC(═S)O, S(═O), SO₂, SO₂NR, NRSO₂,NRCONR′, NRC(═S)NR′, or (CH₂)_(n)O, wherein n=0-6, and wherein R and R′are independently H, alkyl, heteroalkyl, aryl or heteroaryl;

R₉ is hydrogen, OH, OR″, SR″, NR″R′″, alkyl, aryl, heteroalkyl, orheteroaryl, and wherein R″ and R′″ are independently H, alkyl,heteroalkyl, aryl or heteroaryl;

R₁₀ is alkyl, heteroalkyl, aryl or heteroaryl; and

X=O, S.

Further provided are compounds of formula 13:

wherein:

R₇ is aryl or heteroaryl;

R₈ is C₁-C₇ alkyl, C₁-C₇ alkenyl, C₁-C₇ alkynyl, NR, O, S, C(═O)NR,NRC(═O), C(═O), C(═O)O, OC(═O), OC(═O)NR, NRC(═O)O, C(═S)NR, NRC(═S),C(═S), C(═S)O, OC(═S), OC(═S)NR, NRC(═S)O, S(═O), SO₂, SO₂NR, NRSO₂,NRCONR′, NRC(═S)NR′, or (CH₂)_(n)O, wherein n=0-6, and wherein R and R′are independently H, alkyl, heteroalkyl, aryl or heteroaryl;

R₉ is hydrogen, OH, OR″, SR″, NR″R′″, alkyl, aryl, heteroalkyl, orheteroaryl, and wherein R″ and R′″ are independently H, alkyl,heteroalkyl, aryl or heteroaryl; and

R₁₀ is hydrogen, thiol, alkyl, heteroalkyl, aryl or heteroaryl.

Synthesis of Oxazolidinones

Oxazolidinones such as 3-(heteroaryl)oxazolidinones may be synthesizedby a variety of routes as disclosed herein. Exemplary methods ofsynthesis of oxazolidinone compounds are described in U.S. patentapplication Ser. No. 09/012,535, filed Jan. 23, 1998, U.S. patentapplication Ser. No. 09/086,702, filed May 28, 1998, U.S. patentapplication Ser. No. 09/235,771, filed Jan. 22, 1999, andPCT/US99/01318, filed Jan. 22, 1999, the disclosures of which areincorporated herein by reference in their entirety.

In one embodiment, oxazolidinone compounds can be synthesized by:attaching a plurality of aryl or heteroaryl oxazolidinones to aplurality of solid supports; functionalizing the substituents in aryl orheteroaryl groups of the attached oxazolidinones; removing theoxazolidinones from the solid supports in form of5-aminomethyloxazolidinones; and functionalizing the amino group ofcleaved 5-aminomethyloxazolidinones with an appropriate thioacylatingreagent(s) to produce 5-(thiocarbonyl)aminooxazolidinone derivatives.

The final thioacylation step can be performed, e.g., with alkyldithiocarboxylate. The final thioacylation step can be performed, forexample, with a polymeric reagent of the structure

wherein R is an alkyl, aryl, heteroaryl, alkoxy, alkylthio, or aminogroup;

X is O, S, N-(alkoxy)amine, benzotriazole, benzimidazolone, imidazole,or alike electron withdrawing N-heterocyclic group; and

the polymer carrier is polystyrene, polyethyleneglycol (PEG), PEGgrafted polystyrene, or alike polymer.

The polymeric thioacylating reagent can be produced by thioacylation ofan alcohol, thiol, or NH-functionalized polymer carrier. The polymericthioacylating reagent can be produced by stepwise reaction involving (i)acylation of NH-functionalized polymer, and (ii) conversion of the amideintermediate into reactive thioamide with thionation reagents, such asLawesson, Davy, Yokoyama, or Belleau reagents, Na₂P₄S₁₁, Na₂P₄S₁₀O, oralike known compounds capable of converting amides into thioamides. Thepolymeric thioacylating reagent can be produced by reaction ofdithiocarboxylates with appropriate polymeric alkylation reagents, suchas chloroalkyl functionalized resins.

In another embodiment, a method of preparing an oxazolidinone compoundis provided, the method comprising: attaching an aryl or heteroaryloxazolidinone to a solid support to form a linkage between a functionalgroup on the support and the nitrogen of a 5-aminomethyl group of theoxazolidinone; acylating the 5-aminomethyloxazolidinone group of theattached oxazolidinone to form a 5-amidomethyl group; functionalizing asubstituent in an aryl or heteroaryl group of the attachedoxazolidinone; converting the 5-amidomethyl group of an attachedoxazolidinone into a 5-thioamido group; and removing the5-thioamidomethyloxazolidinone from the polymer carrier.

In another embodiment, a method for a solid phase synthesis ofoxazolidinone compounds is provided comprising the treatment of an amideprecursor comprising a group such as NC(O)R₁₀, immobilized on a support,wherein R₁₀ is a substituent such as alkyl, heteroalkyl, aryl orheteroaryl, with a thionation reagent; and release of a compound offormula 3 from the support. One embodiment is illustrated in Scheme 2below.

Synthetic Schemes

Embodiments of schemes for synthesis of oxazolidinone compounds areshown below by way of example. Based on the disclosure herein a widevariety of oxazolidinones as defined herein may be synthesized. Thespecific structures, such as the fluorophenyl ring, are shown by way ofexample, and are not to be considered to be limiting. The synthesis maybe readily conducted with other starting materials, including compoundscomprising other substituted or unsubstituted phenyl rings.

As illustrated in Scheme 1, below, for example, N-substituted5-(S)-aminomethyloxazolidinones can be produced by transformations of5-(S)-aminomethyloxazolidinones with various known electrophilicreagents capable of reacting with a primary or secondary amines with orwithout use of organic or inorganic bases.

In one embodiment, such syntheses can be performed in solution using5-(S)-aminomethyloxazolidinone derivatives as primary amine reagents. Inanother embodiment, 5-(S)-aminomethyloxazolidinone or5-(S)-azidomethyloxazolidinones can be first immobilized on polymericsupports using appropriate linker groups (e.g., aldehyde or benzylhalide-type acid- or photo-cleavable linkers) to produce an immobilized5-(S)-aminomethyloxazolidinone. The latter functionalized compounds canbe treated with appropriate electrophilic reagents to introduce thedesired N-substituent(s). Resulting tethered products can be releasedfrom supports using cleavage reagents (e.g., trifluororacetic acid) orlight (when photocleavable linkers are employed).

The synthesis is shown generally below in Scheme 1a.

In another embodiment, the resulting tethered N-substituted5-(S)-aminomethyloxazolidinone derivatives can be subjected to variouschemical transformations in other parts of the molecule prior to thecleavage from supports, analogously to such transformations ofimmobilized 5-(S)-amidomethyloxazolidinones as described in U.S patentapplication Ser. No. 09/235,771 (PCT/US99/0138).

Embodiments for the synthesis of 5(S)thioamidomethyloxazolidinonederivatives are shown below in Scheme 2.

Exemplary synthetic routes are also shown generally below in Scheme 2a.

In one embodiment, 5-(S)-thioamidomethyloxazolidinone derivatives can beproduced in solution by transformation of5-(S)-aminomethyloxazolidinones with various electrophilic reagentscapable of thioacylation of the primary amine groups.

In another embodiment, 5-(S)-aminomethyloxazolidinones can be firstacylated to produce 5-(S)-amidomethyloxazolidinones intermediates. Thelatter then can be converted into desired thioamides using variousthionation reagents, such as Lawesson, Dayy, Yokayama or Belleaureagents. For a decription of Lawesson reagents, se M. P. Cava, M. I.Levinson, Tetrahedron (1985), 41:5061. For a description of Davyreagents, see H. Davy, Chem. Commun., (1982) p. 457. For a descriptionof Yokoyama reagents, see M. Yokoyama et al., Synthesis, (1984) p. 827.For a description of Belleau reagents, see Tetrahedron Lett., 1983, 24,p. 3815. For a decription of Heimgartner reagents, see P. Wipf, C.Jenny, and H. Heimgartner. Helv. Chim. Acta, (1987) 70, p. 1001. For adescription of P₄S₁₀ and related reagents, see E. Campaigne, TheChemistry of the Carbonyl Group (Ed. S. Patai), Chap. 17. Interscience,New York, 1966. For a description of Na₂P₄S₁₁ reagents, see D. Brillon.,Synth. Commun., (1992) 22, p. 1397. For a description of Na₂P₄S₁₀Oreagents, see D. Brillon, Synth. Commun., (1990), 20, p. 3085. Thedisclosure of these and all other publications referred to herein areincorporated herein by reference in their entirety.

In another embodiment, the thionation step can be performed onimmobilized 5-(S)-amidomethyloxazolidinones. Resulting products can bereleased from supports using chemical cleavage reagents (such as TFA foracid-cleavable resins) or light (when photocleavable linker resin isemployed).

Another illustrative example of a general synthetic scheme for thesynthesis of substituted aminomethyl-3-aryloxazolidinone compounds isshown below in scheme 3a.

In another embodiment, either tethered5-(S)-thioamidomethyloxazolidinone derivatives or their5-(S)-amidomethyl-oxazolidinone precursors can be subjected to variouschemical transformations on solid supports prior to the cleavage ortransformation into thioamides analogously to such reactions ofimmobilized 5-(S)-amidomethyloxazolidinones described in U.S. patentapplication Ser. No. 09/235,771).

In another example, oxazolidinone compounds are synthesized in part on asolid support as shown below in scheme 3:

5-(S)-aminomethyloxazolidinone derivatives can be immobilized onpolymeric supports to produce reactive tethered intermediates. Thelatter can be further modified in various part of the molecule usingfunctional group transformations to derive the desired structures. Thesecan be cleaved from a support in form of the novel5-(S)-aminomethyloxazolidinone structures that can be converted intothioamides using various thioacylating reagents as described for asolution synthesis of such compounds.

In another embodiment, oxazolidinone compounds can be synthesized asshown below in Scheme 4.

For example, 5-(S)-aminomethyloxazolidinone derivatives can be reactedwith Wang or Sasrin imidazole carbamate resins to produce oxazolidinonesimmobilized via acid cleavable carbamate linkage.5-(S)-Aminomethyloxazolidinone can be released from such supports by TFAtreatment and further converted into thioamide derivatives viathioacylation with alkyl dithiocarboxylate reagents in solution.

Scheme 5 below shows an example of the synthesis of an oxazolidinonethioamide using a polymeric thioacylating agent:

Transformation of 5-(S)-aminomethyloxazolidinones into thioamides can beeffected using polymeric thioacylating reagents to provide an advantageof easy products separation. In one embodiment, this can be performedusing dithiocarboxylate resin derivatives.

In one embodiment, polymeric thioacylating reagents can be produced bythioacylation of suitable OH, SH, or NH-functionalized supports withreagents capable of this transformation in solution phase, as shownbelow in Scheme 6.

In another embodiment, polymeric thioacylating reagents can be producedby alkylation of dithiocarboxylate salts with a polymeric supportcomprising reactive alkylation functionalities, such as benzyl or alkylchloride groups, as shown below in Scheme 7.

Scheme 8 below shows the general synthesis of polymeric thioacylatingagents.

Thioacylating polymeric reagents can be produced by transformation ofsuitable immobilized amides into thioamides using thionation reagents,such as Lawesson, Davy, Yokoyama, or Belleau reagents, phosphoruspentasulfide and other chemicals capable of the transformation.Resulting thioamides comprising a thiocarbonyl group attached to anelectron withdrawing nitrogen atom can be used to thioacylate theprimary amine group of 5-(S)-aminomethyloxazolidinone derivatives.

An example of the use of polymeric thioacylating reagents in thepreparation of oxazolidinones is shown below in Scheme 9.

Polymeric thioacylating reagents can be produced by thioacylation of analcohol group functionalized polymers. Resulting thionoester resin canbe used to effect the conversion of 5-(S)-aminomethyloxazolidinones intoreactive thioamide derivatives.

Examples of the use of polymeric thioacylating agents for thepreparation of oxazolidinones is shown below in Scheme 10.

The thioacylating reagent can be made from Grignard reagents, carbondisulfide, and chloroalkyl functionalized polymer, such aspolyethyleneglycol grafted polystyrene, cross-linkeddivinylbenzene-polystyrene, and other similar polymeric materials.

As shown in Scheme 11 below, in another embodiment,5-(S)-aminomethyloxazolidinone derivatives can be immobilized on apolymeric support(s) with a suitable linker functionality (such asaldehyde or benzyl chloride type group) and then acylated to produceimmobilized 5-(S)-amidomethyloxazolidinone derivatives. These tetheredamide intermediates can be converted into thioamides on a solid phaseusing thionation reagents capable of transformation of a secondary aminegroup into thioamide functionality.

Resulting products can be released from the support using chemical orphoto-cleavage depending on the nature of the linker group.

For example, as shown below in Scheme 12, BAL linker immobilized5-(S)-amidomethyl-3-[4′-morpholino-3′-fluoro]phenyloxazolidine-2-one wasconverted into respective thioamide using Lawesson reagent in dioxane.The resulting product was released from the support using TFA cleavage.

As will be appreciated by those skilled in the art, using these andother methods disclosed herein, based on the teachings of thespecification, the oxazolidinones disclosed herein can be readilysynthesized.

Solid Supports

The solid phase synthesis of the compositions provided herein in oneembodiment is performed on a solid support. “Solid support” includes aninsoluble substrate that has been appropriately derivatized such that achemical module can be attached to the surface of the substrate throughstandard chemical methods. Solid supports include, but are not limitedto, beads and particles such as peptide synthesis resins. For example,see Merrifield (1963) J. Am. Chem. Soc. 85:2149-2154; U.S. Pat. No.4,631,211; and Geysen et al. (1984) Proc. Natl. Acad. Sci. USA81:3998-4002.

Solid supports can consist of many materials, limited primarily by thecapacity of the material to be functionalized through synthetic methods.Examples of such materials include, but are not limited to, polymers,plastics, resins, polysaccharides, silicon or silica based materials,carbon, metals, inorganic glasses and membranes. Preferred resinsinclude Sasrin resin (a polystyrene resin available from BachemBioscience, Switzerland), Wang resin or p-nitrophenylcarbonate Wangresin (PNP resin, Novabiochem), and TentaGel S AC, TentaGel PHB, orTentaGel S NH₂ resin (polystyrene-polyethylene glycol copolymer resinsavailable from Rapp Polymere, Tubingen, Germany or from Perseptive,Boston).

The solid support can be purchased with suitable functionality alreadypresent such that a chemical module can be attached to the supportsurface (e.g., Novabiochem, Bachem Bioscience, Rapp Polymere).Alternatively, the solid support can be chemically modified such that achemical module can be attached to the support surface. Grant (1992)Synthetic Peptides. A User's Guide, W. H. Freeman and Co.; and Hermkenset al. (1996) Tetrahedron 52:4527-4554. One of ordinary skill in the artwill understand that the choice of functionality used for attaching amolecule to the solid support will depend on the nature of the compoundto be synthesized and the type of solid support. Examples offunctionality present on the solid support that can be used to attach achemical module include, but are not limited to, alkyl or aryl halides,aldehydes, alcohols, carbonates, ketones, amines, sulfides, carboxylgroups, aldehyde groups and sulfonyl groups.

The functional group on the solid support that permits the attachment ofa chemical module is, for example, an alcohol, an amine, an aldehyde, acarbonate, or a diol group. Gordon et al. (1994) J. Med. Chem.37:1385-1401; and Hermkens et al. (1996) Tetrahedron 52:4527-4554.

For making certain combinatorial libraries, one can purchase a solidsupport with an existing, protected chemical module already attached. Anexample of such a support is FmocGly Sasrin, which is commerciallyavailable from Bachem. Typically, however, the first step of thecombinatorial library synthesis is the attachment of a chemical moduleto the solid support through the existing functionality on the supportsurface. Examples of chemical reactions that can be used to attach achemical module to the support include, but are not limited to,nucleophilic displacement of a halide or other leaving group,etherification of an alcohol, esterification of an alcohol, amidation ofan amine, carbamation of an amine, reductive amination of a carbonylcompound, acetalization of an aldehyde and ketalization of a ketone.Hermkens et al. (1996) Tetrahedron 52:4527-4554.

The reaction used to attach the chemical module to the solid support is,for example, a carbamation of an amine, a reductive amination of acarbonyl compound or a nucleophilic displacement of a halide or otherleaving group. For example, see Hermkens et al. (1996).

For the attachment of certain chemical modules to the solid support, itmay be necessary to mask functionality that is not involved in theattachment process, but that is incompatible with the mode ofattachment. A non-limiting example of this type of process is theesterification of an alcohol functionalized solid support, using ahydroxyl-substituted carboxylic acid as the coupling partner. Prior tothe esterification reaction, the hydroxyl group of the carboxylic acidwould be “protected” through alkylation, silylation, acetylation, orthrough another method known to one of skill in the art. Strategies forthe use of masking or protecting groups have been well-described in theart, such as in Green (1985) Protecting Groups in Organic Synthesis,Wiley.

Methods of Compound Cleavage from a Solid Support

The cleavage of oxazolidinones from a solid support to produce thecorresponding “free” compounds can be accomplished using a variety ofmethods. For example, a compound can be photolytically cleaved from asolid support (Wang et al. (1976) J. Org. Chem. 41:3258; Rich et al.(1975) J. Am. Chem. Soc. 97:1575-1579), and through nucleophilic attack(U.S. Pat. No. 5,549,974), or through hydrolysis (Hutchins et al. (1994)Tetrahedron Lett. 35:4055-4058). The cleavage of compounds from a solidsupport to produce soluble compounds is accomplished, for example, usinghydrolytic conditions, such as through the addition of trifluoroaceticacid.

Screening

The oxazolidinone compounds can be screened to identify bioactivemolecules with different biological activities using methods availablein the art. The bioactive molecules, for example, can possess activityagainst a cellular target, including but not limited to enzymes andreceptors, or a microorganism. A target cellular ligand or microorganismis one that is known or believed to be of importance in the etiology orprogression of a disease. Examples of disease states for which compoundscan be screened for biological activity include, but are not limited to,inflammation, infection, hypertension, central nervous system disorders,and cardiovascular disorders.

In one embodiment of screening, for example, an enzyme solution can bemixed with a solution of the compound(s) under conditions favorable toenzyme-ligand binding. See Bush et al. (1993) Antimicrobial Agents andChemotherapy 37:851-858; and Daub et al. (1989) Biochemistry27:3701-3708. Specific binding of compounds to the enzyme can bedetected, for instance, by any of the numerous enzyme inhibition assayswhich are well known in the art. Compounds which are bound to the enzymeare separated readily from compounds which remain free in solution byapplying the solution to a suitable separation material such as SephadexG-25 gel filtration column. Free enzyme and enzyme-ligand complexes passthrough the column quickly, while free compounds are retarded in theirprogress through the column. The mixture of enzyme-ligand complex andfree enzyme is then treated with a suitable denaturing agent, such asguanidinium hydrochloride or urea, to cause release of the ligand fromthe enzyme. The solution is then injected onto an HPLC column (forexample, a Vydac C-4 reverse-phase column, and eluted with a gradient ofwater and acetonitrile ranging from 0% acetonitrile to 80%acetonitrile). Diode array detection provides discrimination of thecompounds of the combinatorial library from the enzyme. The compoundpeaks are then collected and subjected to mass spectrometry foridentification.

Finding a compound that inhibits an enzyme is performed most readilywith free compound in solution. The compounds can also be screened whilestill bound to a resin used for synthesis; in some applications, thismay be the preferable mode of finding compounds with the desiredcharacteristics. For example, if a compound that binds to a specificantibody is desired, the resin-bound library of compounds is contactedwith an antibody solution under conditions favoring a stableantibody-compound-resin complex. A fluorescently labeled second antibodythat binds to the constant region of the first antibody is thencontacted with the antibody-compound-resin complex. This allowsidentification of a specific bead as carrying the compound recognized bythe first antibody binding site. The bead is then physically removedfrom the resin mixture and subjected to mass spectral analysis. If thesynthesis is conducted in a manner such that only one compound is likelyto be synthesized on a particular bead, then the binding compound hasbeen identified. If the synthesis is carried out so that many compoundsare present on a single bead, the information derived from analysis canbe utilized to narrow the synthetic choices for the next round ofsynthesis and identification.

The enzyme, antibody, or receptor target need not be in solution.Antibody or enzyme can be immobilized on a column. The compound(s) isthen passed over the column, resulting in the retention of stronglybinding compounds on the column after weaker-binding and non-bindingcompounds are washed away. The column is then washed under conditionsthat dissociate protein-ligand binding, which removes the compoundsretained in the initial step. These compounds are then analyzed, andsynthesized separately in quantity for further testing. Similarly, cellsbearing surface receptors are contacted with a solution of compounds.The cells bearing bound compounds are readily separated from thesolution containing non-binding compounds. The cells are then washedwith a solution which dissociates the bound ligand from the cell surfacereceptor. Again, the cells are separated from the solution, and thesolution analyzed.

The compounds also may be assayed for β-lactamase inhibition usingmethods available in the art.

Pharmaceutical Compositions

The present invention also provides pharmaceutical compositions whichcomprise a bioactive oxazolidinone compound or a salt such as apharmaceutically acceptable salt thereof and optionally apharmaceutically acceptable carrier. The compositions include those in aform adapted for oral, topical or parenteral use and can be used for thetreatment of bacterial infection in mammals including humans.

The compounds, such as antibiotic compounds, also referred to herein asantimicrobial compounds, according to the invention can be formulatedfor administration in any convenient way for use in human or veterinarymedicine, by analogy with other bioactive agents such as antibiotics.Such methods are known in the art and are not described in detailherein.

The composition can be formulated for administration by any route knownin the art, such as subdermal, by-inhalation, oral, topical orparenteral. The compositions may be in any form known in the art,including but not limited to tablets, capsules, powders, granules,lozenges, creams or liquid preparations, such as oral or sterileparenteral solutions or suspensions.

The topical formulations of the present invention can be presented as,for instance, ointments, creams or lotions, eye ointments and eye or eardrops, impregnated dressings and aerosols, and may contain appropriateconventional additives such as preservatives, solvents to assist drugpenetration and emollients in ointments and creams.

The formulations may also contain compatible conventional carriers, suchas cream or ointment bases and ethanol or oleyl alcohol for lotions.Such carriers may be present, for example, from about 1% up to about 98%of the formulation. For example, they may form up to about 80% of theformulation.

Tablets and capsules for oral administration may be in unit dosepresentation form, and may contain conventional excipients such asbinding agents, for example syrup, acacia, gelatin, sorbitol,tragacanth, or polyvinylpyrollidone; fillers, for example lactose,sugar, maize-starch, calcium phosphate, sorbitol or glycine; tablettinglubricants, for example magnesium stearate, talc, polyethylene glycol orsilica; disintegrants, for example potato starch; or acceptable wettingagents such as sodium lauryl sulphate. The tablets may be coatedaccording to methods will known in normal pharmaceutical practice.

Oral liquid preparations may be in the form of, for example, aqueous oroily suspensions, solutions, emulsions, syrups or elixirs, or may bepresented as a dry product for reconstitution with water or othersuitable vehicle before use. Such liquid preparations may containconventional additives, such as suspending agents, for example sorbitol,methyl cellulose, glucose syrup, gelatin, hydroxyethyl cellulose,carboxymethyl cellulose, aluminium stearate gel or hydrogenated ediblefats, emulsifying agents, for example lecithin, sorbitan monooleate, oracacia; non-aqueous vehicles (which may include edible oils), forexample almond oil, oily esters such as glycerine, propylene glycol, orethyl alcohol; preservatives, for example methyl or propylp-hydroxybenzoate or sorbic acid, and, if desired, conventionalflavoring or coloring agents.

For parenteral administration, fluid unit dosage forms are preparedutilizing the compound and a sterile vehicle, water being preferred. Thecompound, depending on the vehicle and concentration used, can be eithersuspended or dissolved in the vehicle or other suitable solvent. Inpreparing solutions, the compound can be dissolved in water forinjection and filter sterilized before filling into a suitable vial orampoule and sealing. Advantageously, agents such as a local anestheticpreservative and buffering agents can be dissolved in the vehicle. Toenhance the stability, the composition can be frozen after filling intothe vial and the water removed under vacuum. The dry lyophilized powderis then sealed in the vial and an accompanying vial of water forinjection may be supplied to reconstitute the liquid prior to use.Parenteral suspensions are prepared in substantially the same mannerexcept that the compound is suspended in the vehicle instead of beingdissolved and sterilization cannot be accomplished by filtration. Thecompound can be sterilized by exposure to ethylene oxide beforesuspending in the sterile vehicle. Advantageously, a surfactant orwetting agent is included in the composition to facilitate uniformdistribution of the compound.

The compositions may contain, for example, from about 0.1% by weight,e.g., from about 10-60% by weight, of the active material, depending onthe method of administration. Where the compositions comprise dosageunits, each unit will contain, for example, from about 50-500 mg of theactive ingredient. The dosage as employed for adult human treatment willrange, for example, from about 100 to 3000 mg per day, for instance 1500mg per day depending on the route and frequency of administration. Sucha dosage corresponds to about 1.5 to 50 mg/kg per day. Suitably thedosage is, for example, from about 5 to 20 mg/kg per day.

Pharmaceutical Applications

The oxazolidinones disclosed herein can be used in a variety ofpharmaceutical applications. In one embodiment, the compounds may beused as antimicrobial agents for the treatment of infectious disordersthat are caused by microbial agents, such as bacteria.

In one embodiment, compositions, for treating or preventing infectiousdisorders are provided, comprising an oxazolidone compound as disclosedherein in combination with a pharmaceutically acceptable carrier.

In another embodiment, there is provided a dosage amount of anoxazolidinone as disclosed herein in an effective amount for thetreatment, prevention or alleviation of a disorder, such as aninfectious disorder.

Oxazolidinones can be screened for activity against different microbialagents and appropriate dosages may be determined using methods availablein the art.

The compounds may be used to treat a subject to treat, prevent, orreduce the severity of an infection. Subjects include animals, plants,blood products, cultures and surfaces such as those of medical orresearch equipment, such as glass, needles and tubing.

In one embodiment, methods of treating or preventing an infectiousdisorder in a subject, such as a human or other animal subject, areprovided, by administering an effective amount of an oxazolidinone asdisclosed herein to the subject. In one embodiment, the compound isadministered in a pharmaceutically acceptable form optionally in apharmaceutically acceptable carrier. As used herein, an “infectiousdisorder” is any disorder characterized by the presence of a microbialinfection, such as bacterial infections. Such infectious disordersinclude, for example central nervous system infections, external earinfections, infections of the middle ear, such as acute otitis media,infections of the cranial sinuses, eye infections, infections of theoral cavity, such as infections of the teeth, gums and mucosa, upperrespiratory tract infections, lower respiratory tract infections,genitourinary infections, gastrointestinal infections, gynecologicalinfections, septicemia, bone and joint infections, skin and skinstructure infections, bacterial endocarditis, burns, antibacterialprophylaxis of surgery, and antibacterial prophylaxis inimmunosuppressed patients, such as patients receiving cancerchemotherapy, or organ transplant patients. The compounds andcompositions comprising the compounds can be administered by routes suchas topically, locally or systemically. Systemic application includes anymethod of introducing the compound into the tissues of the body, e.g.,intrathecal, epidural, intramuscular, transdermal, intravenous,intraperitoneal, subcutaneous, sublingual, rectal, and oraladministration. The specific dosage of antimicrobial to be administered,as well as the duration of treatment, may be adjusted as needed.

The compounds of the invention may be used for the treatment orprevention of infectious disorders caused by a variety of bacterialorganisms. Examples include Gram positive and Gram negative aerobic andanaerobic bacteria, including Staphylococci, for example S. aureus;Enterococci, for example E. faecalis; Streptococci, for example S.pneumoniae; Haemophilus, for example H. influenza; Moraxella, forexample M. catarrhalis; and Escherichia, for example E. coli. Otherexamples include Mycobacteria, for example M. tuberculosis;intercellular microbes, for example Chlamydia and Rickettsiae; andMycoplasma, for example M. pneumoniae.

The following examples are provided to illustrate but not limit theclaimed invention.

EXAMPLES

Abbreviations: ACN, acetonitrile; CDI, carbonyldiimidazole; DIEA,diethylisopropylamine; DCM, dichloromethane; DIC, diisopropyldiimide;DMF, dimethylformamide; HATU,O-(7-azabenzotriazol-1-yl)-1,1,3,3-bis(tetramethylene)-uroniumhexafluorophosphate; NMM, N-methyl morpholine; mCPBA,m-chloro-peroxybenzoic acid; TFA, trifluoroacetic acid; THF,tetrahydrofuran; TMOF, trimethylorthoformate; PTLC, preparative thinlayer chromatography.

General. Reagents were obtained from Aldrich (St. Louis, Mo), Sigma (St.Louis, Mo.), Bachem Biosciences, Rapp Polymere, Perseptive, andNovabiochem, and used without further purification. The resin Tentagel SNTi was purchased from Rapp Polymere. Concentration of solutions afterworkup was performed by reduced pressure rotary evaporation, or usingthe Savant's SpeedVac instrument. Reactions with moisture-sensitivereagents were performed under nitrogen atmosphere.

Mass-spectra were obtained using ESI technique. HTLC analysis andpurification were performed using Beckman System Gold R®; detection at220 nm. Analytical EPLC was performed on YMC 5 micron C18 (4.6 mm×50 mm)reverse phase column (gradient from 100% of the aq. 0.1% TFA to 100% of0.1% TFA in MECN over 6 min, flow rate 2.0 mL/min). Preparative TLC wasperformed using EM silica gel 60 F₂₅₄ plates (20×20 cm, thickness 2min).

NMR spectra were obtained on a Varian Gemini 300 MHz instrument withCDCl₃ as solvent, unless otherwise noted. 1H NMR spectra were reportedas follows: chemical shift relative to tetramethylsilane (0.00 ppm),multiplicity (s=singlet, d=doublet, t=triplet, q=quartet, m=multiplet,b=broad), coupling, and integration.

Example 1

General Methods for Preparation of 5-(S)-Thioamidomethyloxazolidinones

A. Synthesis from 5-(S)-Aminomethyloxazolidinone Derivatives and EthylDithioacetate

A solution of an appropriate 5-(S)-aminomethyloxazolidinone derivative(1.0 mmol) and ethyl dithioacetate (0.130 ml, 1.13 mmol) withtriethylamine (0.215 ml,1.54 mmol) in dichloromethane was stirred atroom temperature overnight. The reaction mixture was concentrated undervacuum and the residue purified by PTLC (MeOH-DCM mixtures) orcrystallization from appropriate solvent.

B. Synthesis from 5-(S)-Amidomethyloxazolidinone Derivatives andLawesson Reagent

A mixture of an appropriate 5-(S)-amidomethyl-oxazolidinone derivative(0.3 mmol) and Lawesson's reagent (0.0654 g, 0.15 mmol) in dioxane (3ml) was stirred and heated at 65° C. for 2 hours. The solution wasconcentrated under vacuum and the crude product purified by PTLC.

C. Solid Phase Synthesis from Immobilized5-(S)-Amidomethyl-oxazolidinone Derivatives

A mixture of an appropriate 5-(S)-amidomethyloxazolidinone immobilizedderivative (such as described in U.S. patent application Ser. No.09/235,771 and in PCT US99/01318) (0.1 mmol) and an appropriatethionation reagent (0.1-1.0 mmol) in dioxane or THF (2-10 mL) Lawesson'sreagent (0.15 was stirred at 0-65° C. for 2-10 hours (preferably, at0-25° C. for P₄S₁₀, Na₂P₄S₁₁ or Na40-65° C. for Lawesson, Belleau, orDavy reagents). The resin was washed liberally with DMF, DCM, MeOH, anddried under vacuum. The product was cleaved from support with 10% TFA inDCM (2-4 mL, r.t., 2 h), solvents removed under vacuum, and the crudeproduct purified by PTLC.

Example 2

Synthesis of Intermediates

2-Fluoro-4-nitrobenzoic Acid

Concentrated sulfuric acid (32 ml) was added carefully with stirring toa solution of 2-fluoro-4-nitrotoluene (16.5 g, 0.106 mol) in acetic acid(200 ml). The mixture was warmed up to 95° C., and solution of chromiumtrioxide (37.1 g, 0.371 mol) in water (32 ml) was added dropwise withstirring over 2 h. The mixture was heated with stirring for another 30minutes, allowed to cool down to r.t., and poured into water (1000 ml).The product was extracted with diethyl ether (3×200 ml). Combined etherlayers were washed with water and evaporated to dryness. The residue wasdissolved in 10% aqueous potassium carbonate and washed with ether. Theaqueous layer was acidified with con. HCl, and the resulting whiteprecipitate filtered and dried (16.3 g, 83%), m.p. 174-177° C.

tert-Butyl 2-fluoro-4-nitrobenzoate

Thionyl chloride (45 ml, 0.62 mol) was added to 2-fluoro-4-nitrobenzoicacid (23.0 g, 0.124 mol), and the mixture was stirred under reflux for 2h. Solvent was removed under vacuum, and the residue thoroughly driedunder vacuum to give crystalline acid chloride (25.2 g, 99%). The acidchloride was dissolved in tetrahydrofuran (150 ml) under nitrogen, and1M lithium tert-butoxide in tetrahydrofuran (136 ml, 0.136 mol) wasadded dropwise with stirring at room temperature. The mixture wasstirred overnight, diluted with water (300 ml) and extracted with ether.The ether layer was washed with saturated aqueous sodium bicarbonate,brine, and dried (MgSO₄). Solvent was removed under vacuum to gave theproduct as a white crystalline solid (24.2 g, 81%); mp 81-82° C.

tert-Butyl-2-fluoro-4-aminobenzoate

Tert-butyl 2-fluoro-4-nitrobenzoate (24.2 g, 0.100 mol) was added to awarm (95° C.) solution of ammonium chloride (53.5 g, 1.00 mol),dissolved in ethanol (300 ml) and water (150 ml). Iron powder (325 mesh,16.8 g, 0.300 mol) was added with stirring in small portions over about1 h. The reaction mixture was stirred and heated at 95° C. for another30 minutes and then filtered while still warm. The filter cake waswashed thoroughly with excess ethanol. The filtrate and washings werediluted with water (1 L) and extracted with ether (3×150 ml).

Combined ether extracts were washed with water and brine, dried (MgSO₄),and evaporated to give the product as an off-white solid (21.1 g, 98%);mp 100-101° C.

O-Benzyl-N-(3-fluoro-4-butoxycarbonylphenyl)carbamate.

Benzyl chloroformate (15.9 ml, 0.1 12 mol) was added dropwise withstirring to a mixture of tert-butyl-2-fluoro-4-aminobenzoate (21.5 g,0.102 mol) and pyridine (16.5 ml, 0.204 mol) in dichloromethane (200 ml)at 0° C. The reaction mixture was stirred for 30 minutes at 0° C.,allowed to warm up to room temperature, and then poured into water(about 300 ml). The organic layer was separated, washed with water,brine and dried (MgSO₄). Evaporation gave a white solid, which waswashed with hexane and dried under vacuum to afford the product (32.8 g,93%); mp 117-118° C.

5-(R)-Hydroxymethyl-3-[4′-tert-butoxycarbonyl-3′-fluorophenyl]oxazolidine-2-one

1M Lithium bis(trimethylsilyl)amide in tetrahydrofuran (104 ml, 0.104mol) was added dropwise with stirring at −78° C. to a solution ofO-benzyl-N-(3-fluoro-4-butoxycarbonylphenyl)-carbamate (32.8 g, 0.0948mol) in tetrahydrofuran (150 ml). The mixture was stirred at −78° C. for1 hour, and then (R)-glycidyl butyrate (15.0 g, 0.104 mol) was addeddropwise with stirring. The mixture was allowed to warm to roomtemperature overnight, and was then quenched with saturated aqueousammonium chloride (100 ml). The mixture was extracted with ethylacetate, and the combined organic layers washed with water, brine, anddried (MgSO₄). Solvent was removed under vacuum, and the crude productpurified by silica gel column chromatography (eluent: 30% ethyl acetatein hexanes) to afford the product as a white solid (20.0 g, 68%); mp148-149° C.

5-(S)-Azidomethyl-3-[4′-tert-butoxycarbonyl-3′-fluorophenyl]oxazolidine-2-one

Methanesulfonyl chloride (2.61 ml, 0.0337 mol) was added dropwise withstirring to a solution of5-(R)-hydroxymethyl-3-[4′-tert-butoxycarbonyl-3′-fluorophenyl]oxazolidine-2-oxazolidine(10.0 g, 0.0321 mol) and triethylamine (6.71 ml, 0.0482 mol) indichloromethane (150 ml) at 0° C. over about 15 minutes. The reactionmixture was allowed to warm up to room temperature and then poured intowater. The organic layer was separated, washed with water, saturated aq.NaHCO₃, brine, and dried (MgSO₄). Solvent was removed under vacuum toafford the mesylate intermediate as an oil (11.6 g, 99%). A mixture ofthe mesylate (13.4 g, 0.0370 mol) and sodium azide (12.0 g, 0.185 mol)in DMF (130 ml) was heated with stirring at 75° C. for 12 h. Thereaction mixture was cooled to room temperature, diluted with water (300ml), and extracted with ethyl acetate (3×100 ml). Combined organiclayers were washed with water and brine, dried (MgSO₄) and evaporated.The residue was washed with diethyl ether to give the pure azide as awhite solid (9.76 g, 90.5%); mp 91-92° C.

Example 3

5-(S)-Azidomethyl-3-[4′-chlorocarbonyl-3′-fluorophenyl]oxazolidine-2-one

60% TFA in DCM (5 mL) was added to5-(S)-azidomethyl-3-[4′-tert-butoxycarbonyl-3′-fluorophenyl]oxazolidine(0.336 g, 1 mmol), and the solution kept at r.t. for 1 h. Solvents wereremoved in vacuo to afford5-(S)-azidomethyl-3-[4′-carboxy-3′-fluorophenyl-]oxazolidine-2-one dried(0.280 g, 99%). N-Trimethylsilyl-N,N-diethylamine (0.23 mL, 1.2 mmol)was added to above product in dry dichloromethane (3 mL) under nitrogenatmosphere, and the solution stirred for 15 min. Solvents and excessreagent were removed in vacuo, and residue dissolved in dichloromethane(4 mL). The solution was cooled to about 0° C., and oxalyl chloride (1.5mmol, 0.13 mL) was added dropwise, followed by catalyticN,N-dimethylformamide (about 0.01 mL). The mixture was allowed to warmup to r.t. (room temperature), and stirred at r.t. for another 2 h.Solvents were removed in vacuo to afford the product as a white solid.Yield 0.292 g (98%).

5-(S)-Azidomethyl-3-[4′-(6″-chloropyridine-3″-yl)aminocarbonyl-3′-fluoro-phenyl]oxazolidine-2-one

5-(S)-Azidomethyl-3-[4′-chlorocarbonyl-3′-fluorophenyl]oxazolidine-2-one(0.298 g, 1.0 mmol) was added to a solution of 5-amino-2-chloropyridine(0.129 g, 1.0 mmol) in 20% pyridine in THF (2 mL), and the mixturestirred at r.t overnight. Solvent was removed unde vacuum, and theresidue triturated with water. Resulting crude product was washed with3% aq. citric acid, 2% aq. sodium bicarbonate, water, ethyl ether, anddried under vacuum (yield 0.357 g, 91%; ¹HNMR).

5-(S)-Aminomethyl-3-[4′-(6″-chloropyridine-3″-yl)aminocarbonyl-3′-fluoro-phenyl]oxazolidine-2-one

5-(S)-Azidomethyl-3-[4′-(6″-chloropyridine-3″-yl)aminocarbonyl-3′-fluoro-phenyl]oxazolidine-2one(0.35 g, 0.896 mmol) and triphenylphosphine (0.235 g, 0.896 mmol) in THF(10 mL) was stirred at r.t. for 4 h and then at 40° C. for 2 h. Water(0.5 mL) was added, and the mixture stirred at 40° C. overnight.Solvents were removed in vacuo, and resulting crude product washed withethanol and diethyl ether. Yield 0.215 g (66%). ¹H NMR. MS (m/z):[M+H]⁺=365.

5-(S)-Thioacetamidomethyl-3-[4′-(6″-chloropyridine-3″-yl)aminocarbonyl-3′-fluoro-phenyl]oxazolidine-2-one

This compound was prepared analogously to Method A (Example 1) abovefrom5-(S)-aminomethyl-3-[4′-(2″-chloropyridine-5″-yl)aminocarbonyl-3′-fluorophenyl]oxazolidine-2-one(0.125 g, 0.343 mmol) and ethyl dithioacetate. The crude productpurified by PTLC (10% MeOH in DCM). Yield 0.035 g (24%). MS (m/z):[M+H]⁺=421.

Example 4

5-(S)-Azidomethyl-3-[4′-(5″-trifluoromethylpyridine-2″-yl)aminocarbonyl-3′-fluorophenyl]oxazolidine-2-one

This compound was prepared analogously to the synthesis of5-(S)-azidomethyl-3-[4′-(6″-chloropyridine-3″-yl)aminocarbonyl-3′-fluorophenyl]oxazolidine-2-onefrom 2-amino-5-trifluoromethylpyridine (0.100 g, 0.62 mmol) and5-(S)-azidomethyl-3-[4′-chlorocarbonyl-3′-fluorophenyl]oxazolidine-2-one(0.184 g, 0.62 mmol). Yield 0.11 g (42%). MS (m/z): [M+H]⁺=425.

5-(S)-Aminomethyl-3-[4′-(5″-trifluoromethylpyridine-2″-yl)aminocarbonyl-3′-fluorophenyl]oxazolidine-2-one

Preparation was analogous to the synthesis of5-(S)-aminomethyl-3-[4′-(6″-chloropyridine-3″-yl)aminocarbonyl-3′-fluorophenyl]oxazolidine-2-onefrom5-(S)-azidomethyl-3-[4′-(5″-trifluoromethylpyridine-2″-yl)aminocarbonyl-3′-fluorophenyl]oxazolidine-2-one(0.100 g, 0.235 mmol) and triphenylphosphine (0.068 g, 0.259 mmol).Yield 0.087 g (93%). MS (m/z): [M+H]⁺=399.

5-(S)-Thioacetamidomethyl-3-[4′-(5″-trifluoromethylpyridine-2″-yl)amino-carbonyl-3′-fluorophenyl]oxazolidine-2-one

This compound was prepared analogously to the Method A of GeneralMethods for Preparation of 5-(S)-Thioamidomethyloxazolidinones(Example 1) from5-(S)-aminomethyl-3-[4′-(5″-trifluoromethylpyridine-2″-yl)aminocarbonyl-3′-fluorophenyl]oxazolidine-2-one(0.070 g, 0.176 mmol) and ethyl dithioacetate. The crude product waspurified by PTLC (10% MeOH in DCM). Yield 0.020 g (20%). MS (m/z):[M+H]⁺=457.

Example 5

5-(S)-Azidomethyl-3-[4′-(5″-trifluoromethyl-1″,3″,4″-thiadiazole-2″-yl)amino-carbonyl-3′-fluorophenyl]oxazolidine-2-one

Prepared analogously to the synthesis of5-(S)-azidomethyl-3-[4′-(6″-chloropyridine-3″-yl)aminocarbonyl-3′-fluorophenyl]oxazolidine-2-onefrom 2-amino-5-trifluoromethyl-1,3,4-thiadiazole (0.100 g, 0.59 mmol)and5-(S)-azidomethyl-3-[4′-chlorocarbonyl-3′-fluorophenyl]oxazolidine-2-one(0.176 g, 0.59 mmol). Yield 0.093 g (36%). MS (m/z): [M+H]⁺=432.

5-(S)-Aminomethyl-3-[4′-(5″-trifluoromethyl-1″,3″,4″-thiadiazole-2″-yl)ami-nocarbonyl-3′-fluorophenyl]oxazolidine-2-one

Prepared analogously to the synthesis of5-(S)-aminomethyl-3-[4′-(6″-chloropyridine-3″-yl)aminocarbonyl-3′-fluorophenyl]oxazolidine-2-onefrom5-(S)-azidomethyl-3-[4′-(5″-trifluoromethyl-1″,3″,4″-thiadiazole-2″-yl)amino-carbonyl-3′-fluorophenyl]oxazolidine-2-one(0.090 g, 0.209 mmol) and triphenylphosphine (0.055 g, 0.209 mmol).Yield 0.010 g (12%). MS (m/z): [M+H]⁺=406.

5-(S)-Thioacetamidomethyl-3-[4′-(5″-trifluoromethyl-1″,3″,4″-thiadiazole-2″-yl)aminocarbonyl-3′-fluorophenyl]oxazolidine-2-one

Prepared analogously to the Method A of General Methods for Preparationof 5-(S)-Thioamidomethyloxazolidinones (Example 1) from5-(S)-aminomethyl-3-[4′-(5″-trifluoromethyl-1″,3″,4″-thiadiazole-2″-yl)aminocarbonyl-3′-fluorophenyl]oxazolidine-2-one(0.010 g, 0.0247 mmol; prepared analogously to U.S. Pat. No. 09/235,771)and ethyl dithioacetate. The crude product purified by PTLC (10% MeOH inDCM). Yield 0.0035 g (31%). MS (m/z): [M+H]⁺=464.

Example 6

3-Fluoro-4-thiocyanoaniline

N-Bromosuccinimide (1.76 g, 9.89 mmol) and potassium thiocyanate (1.75g, 18.0 mmol) in methanol (30 ml) were stirred for 15 minutes at roomtemperature. The reaction mixture was cooled to 0° C., and3-fluoroaniline (1.00 g, 9.0 mmol) was added dropwise. The mixture wasstirred at 0° C. for 2 h. Solvent was removed under vacuum, and theresidue was washed with dichloromethane. The mixture was filtered toremove succinimide by-product, and the solution was washed with water,brine, and dried (MgSO₄). Solvent was removed under vacuum to afford thedesired product as a colorless oil. Yield 1.45 g (96%).

O-Benzyl -N-[3-fluoro-4-(thiocyano)phenyl]carbamate

Benzyl chloroformate (1.87 ml, 13.1 mmol) was added to a mixture of3-fluoro-4-thiocyanoaniline (2.00 g, 11.9 mmol) and pyridine (2.12 ml,26.2 mmol) in dichloromethane (30 ml) at 0° C. The mixture was stirredfor 30 minutes at 0° C., allowed to warm to room temperature, and thenpoured into water. The organic layer was separated, washed with brine,and dried (MgSO₄). Solvent was removed under vacuum. The crude productwas washed with ether-hexanes and dried under vacuum to afford thedesired product. Yield 3.64 g (92%); m.p. 74-75° C.

O-Benzyl-N-[3-fluoro-4-(triphenylmethylthio)phenyl]carbamate

Sodium sulfide nonahydrate (0.794 g, 3.31 mmol) in water (3 ml) wasadded dropwise at room temperature to a solution ofO-benzyl-N-[3-fluoro-4-(thiocyano)phenyl]carbamate (1.00 g, 3.31 mmol)in ethanol (10 ml). The reaction mixture was stirred at room temperaturefor 30 minutes, and then triphenylmethyl bromide (1.07 g, 3.31 mol) in1,4-dioxane (5 ml) was added dropwise. The reaction was stirredovernight. Organic solvent was removed under vacuum, and the residuetaken up in ethyl acetate. The solution was washed with water, brine,and dried (MgSO₄). Solvent was removed under vacuum, and the crudeproduct purified by silica gel column chromatography (eluent: 10% ethylacetate in hexanes) to give the desired compound as a white solid. Yield1.10 g, (64%); mp 152-153° C.

5-(R)-Hydroxymethyl-3-[4′-triphenylmethylthio-3′-fluorophenyl]oxazolidine-2-one

1M Lithium bis(trimethylsilyl)amide in tetrahydrofuran (54 mL, 69.9mmol) was added dropwise with stirring at −78° C. to a solution ofO-benzyl-N-[3-fluoro-4-(triphenylmethylthio)phenyl]carbamate (33.0 g,63.5 mmol) in tetrahydrofuran (250 ml). The mixture was stirred at −78°C. for 1 hour, and then (R)-glycidyl butyrate (11.0 g, 76.2 mmol) wasadded dropwise with stirring. The mixture was allowed to warm up to roomtemperature overnight, and then quenched with saturated aq. ammoniumchloride (125 ml). The mixture was extracted with ethyl acetate, andcombined organic layers washed with water, brine, and dried (MgSO₄).Solvent was removed under vacuum, and the crude product purified bysilica gel column chromatography (gradient from 30% to 75% of ethylacetate in hexane) to afford the product. TLC: R_(f)0.2 (ethylacetate-hexanes 1:1). MS 486 [M+H]⁺.

5-(S)-Azidomethyl-3-[4′-triphenylmethylthio-3′-fluorophenyl]oxazolidine-2-one

Methanesulfonyl chloride (3.91 mL, 50.6 mmol) was added dropwise withstirring to a solution of5-(R)-hydroxymethyl-3-[4′-triphenylmethylthio-3′-fluorophenyl]oxazolidine-2-one(23.4 g, 48.2 mmol) and triethylamine (10.1 mL, 73.8 mmol) indichloromethane (200 mL) at 0° C. over about 10 minutes. The reactionmixture was allowed to warm up to room temperature and then poured intowater. The organic layer was separated, washed with water, saturated aq.NaHCO₃, brine, and dried (MgSO₄). Solvent is removed under vacuum toafford the mesylate intermediate as an oil (27.2 g, 99%). The mesylate(27.2 g, 48.2 mmol) and sodium azide (15.7 g, 241.0 mmol) in DMF (150ml) was heated with stirring at 70° C. for 12 h. The reaction mixturewas cooled to r.t., diluted with water (750 mL), and extracted withethyl acetate. Combined organic layers were washed with water, brine,and dried (MgSO₄). Solvent was removed under vacuum and the crudeproduct purified by silica gel column chromatography (eluent: 30% ethylacetate in hexanes) to afford the azide product as a white solid. Yield18.1 g (73%). M.p. 77-79° C.

5-(S)-Aminomethyl-3-[4′-triphenylmethylthio-3′-fluorophenyl]oxazolidine-2-one

Triphenylphosphine (2.82 g, 10.8 mmol) was added portionwise to asolution of5-(S)-azidomethyl-3-[4′-triphenylmethylthio-3′-fluorophenyl]oxazolidine-2-one(5.00 g, 9.79 mmol) in THF (40 mL), and the mixture stirred for 2 h atr.t. Water (1.41 mL, 78.3 mmol) was added, and the mixture heated at 40°C. overnight. Solvent was removed under vacuum, and the oily residuepurified by column chromatography (eluent: DCM, then 10% MeOH in DCM).Yield 3.56 g (75%). MS (m/z): [M+H]⁺=485.

5-(S)-Acetamidomethyl-3-[4′-triphenylmethylthio-3′-fluorophenyl]oxazolidine-2-one

Triphenylphosphine (2.82 g, 10.8 mmol) was added portionwise to asolution of5-(S)-azidomethyl-3-[4′-triphenylmethylthio-3′-fluorophenyl]oxazolidine-2-one(5.00 g, 9.79 mmol) in THF (40 mL), and the mixture stirred for 2 h atroom temperature. Water (1.41 mL, 78.3 mmol) was added, and the mixtureheated at 40° C. overnight. Solvent was removed under vacuum, and theoily residue dissolved in dichloromethane (50 mL). Acetic anhydride(4.62 ml, 49.0 mmol) and pyridine (7.92 ml, 97.9 mmol) were added, andthe mixture stirred for 8 h at r.t. Solvent was removed under vacuum andthe crude product purified by silica gel flash column chromatography(eluent: 30% ethyl acetate in hexanes) to give the product as a foam(4.98 g, 97%); MS (m/z): [M+H]⁺=527.

General Procedure for Preparation of5-(S)-(N-Acylaminomethyl)-3-[4′-(Substituted)thio-3′-fluorophenyl]oxazolidine-2-ones

5% TFA and 2.5% triisopropylsilane in dichloromethane (2.0 mL) was addedto5-(S)-acetamidomethyl-3-[4′-triphenylmethylthio-3′-fluorophenyl]oxazoli-dine-2-one(0.10 g, 0.19 mmol), and the mixture was stirred at r.t. for 1 h. andthe mixture stirred for 1 h at room temperature. Solvent was removedunder vacuum, and the residue dissolved in methanol (3 mL). Anappropriate alkylating or (hetero)arylating reagent (19-0.38 mmol) wasadded, followed by dropwise addition of 4.37 M sodium methoxide inmethanol (0.087 ml, 0.380 mmol). Optionally, an organic base was usedinstead of sodium methoxide (e.g., tetramethylguanidine or alkylamine).The mixture was stirred at 20-70° C. for 2-24 h (typically, 2 h atr.t.). Solvent was removed under vacuum and the crude product purifiedby TLC (methanol-dichloromethane mixtures).

Example 7

5-(S)-Acetamidomethyl-3-[4′-(2″-chloroethyl)thio-3′-fluorophenyl]oxazolidi-ne-2-one

Prepared according to the General Procedure for Preparation of5-(S)-(N-Acylaminomethyl)-3-[4′-(substituted)thio-3′-fluorophenyl]oxazolidine-2-ones(Example 6) from5-(S)-acetamidomethyl-3-[4′-(triphenylmethyl)lthio-3′-fluorophenyl]-oxazolidine-2-onewith 1-bromo-2-chloroethane (0.055 g, 0.38 mmol) inN-methylpyrrolidine-2-one (1 mL). The synthesis was performed at r.t.for 2 h. The crude product was purified by TLC (eluent: 10% methanol indichloromethane). Yield 0.047 g (72%). MS (m/z): 347 [M+H]⁺.

5-(S)-Thioamidomethyl-3-[4′-(2″-chloroethyl)thio-3′-fluorophenyl]oxazolidine-2-one

Prepared analogously to the Method B of General Methods for Preparationof 5-(S)-Thioamidomethyloxazolidinones (Example 1) from5-(S)-acetamidomethyl-3-[4′-(2″-chloroethyl)thio-3′-fluorophenyl]oxazolidine-2-one(0.0275 g, 0.0793) and Lawesson reagent. Yield 0.027 g (94%). M.p.134-5° C. MS (m/z): [M+H]⁺=363.

Example 8

5-(S)-Acetamidomethyl-3-[4′-(5″-nitrothiazole-2″-yl)thio-3′-fluorophenyl]-oxazolidine-2-one

Prepared according to the General Procedure for Preparation of5-(S)-(N-Acylaminomethyl)-3-[4′-(substituted)thio-3′-fluorophenyl]oxazolidine-2-ones(Example 6) from5-(S)-acetamidomethyl-3-[4′-(triphenylmethyl)lthio-3′-fluorophenyl]-oxazolidine-2-onewith 2-bromo-5-nitrothiazole (0.079 g, 0.38 mmol) inN-methylpyrrolidine-2-one (1 mL). The synthesis was performed at r.t.for 2 h. The crude product was purified by TLC (eluent: 10% methanol indichloromethane). Yield 0.061 g (78%). MS (m/z): 413 [M+H]⁺.

5-(S)-Thioamidomethyl-3-[4′-(5″-nitrothiazole-2″-yl)thio-3′-fluorophenyl]-oxazolidine-2-one

Prepared analogously to the Method B of General Methods for Preparationof 5-(S)-Thioamidomethyloxazolidinones (Example 1) from5-(S)-acetamidomethyl-3-[4′-(5″-nitrothiazole-2″-yl)thio-3′-fluorophenyl]oxazolidine-2-one(0.028 g, 0.0736 mmol) and Lawesson reagent. Yield 0.026 g (83%). M.p.116-7° C. MS (m/z): [M+H]⁺=429.

Example 9

5-(S)-Acetamidomethyl-3-(4′-methylthio-3′-fluorophenyl]oxazolidine-2-one

Prepared according to the General Procedure for Preparation of5-(S)-(N-Acylaminomethyl)-3-[4′-(substituted)thio-3′-fluorophenyl]oxazolidine-2-ones(Example 6) from5-(S)-acetamidomethyl-3-[4′-(triphenylmethyl)lthio-3′-fluorophenyl]-oxazolidine-2-onewith methyl iodide (0.05 mL, 0.81 mmol) in N-methylpyrrolidine-2-one (1mL). The synthesis was performed at r.t. overnight, and the crudecleaved product purified by TLC (eluent: 10% methanol indichloromethane). Yield 6.3 mg (52%). MS: 299 [M+H]⁺.

5-(S)-Thioamidomethyl-3-[4′-methylthio-3′-fluorophenyl]-oxazolidine-2-one

Prepared analogously to the Method B (Example 1) of General Methods forPreparation of 5-(S)-Thioamidomethyloxazolidinones from5-(S)-acetamidomethyl-3-[4′-methylthio-3′-fluorophenyl]oxazolidine-2-one(0.100 g, 0.335 mmol) and Lawesson reagent. Yield 0.095 g (90%). M.p.130-1° C. MS (m/z): [M+H]⁺=315.

Example 10

5-(S)-Thioamidomethyl-3-[4′-(triphenylmethyl)thio-3′-fluorophenyl]oxazoli-dine-2-one

Prepared analogously to the Method A of General Methods for Preparationof 5-(S)-Thioamidomethyloxazolidinones (Example 1) from5-(S)-aminomethyl-3-[4′-(triphenylmethyl)thio-3′-fluorophenyl]-oxazolidine-2-one(0.500 g, 1.03 mmol; prepared analogously to U.S. Pat. No. 09/235,771)and ethyl dithioacetate. Reaction performed in DCM overnight. Yield0.498 g (89%). MS (m/z): [M+H]⁺=543.

Example 11

5-(S)-Acetamidomethyl-3-[4′-(2″-hydroxyethyl)thio-3′-fluorophenyl]oxazo-lidine-2-one

Prepared according to the General Procedure for Preparation of5-(S)-(N-Acylaminomethyl)-3-[4′-(substituted)thio-3′-fluorophenyl]oxazoli-dine-2-ones(Example 6) from5-(S)-acetamidomethyl-3-[4′-(triphenylmethyl)lthio-3′-fluorophenyl]-oxazolidine-2-onewith 2-bromoethanol (0.048 g, 0.38 mmol) in N-methylpyrrolidine-2-one (1mL). The synthesis was performed at r.t. for 2 h. The crude product waspurified by TLC (eluent: 10% methanol in dichloromethane). Yield 0.045 g(72%). MS (m/z): 329 [M+H]⁺.

5-(S)-Thioamidomethyl-3-[4′-(2″-hydroxyethyl)thio-3′-fluorophenyl]oxazo-lidine-2-one

A solution of5-(S)-thioamidomethyl-3-[4′-(triphenylmethyl)thio-3′-fluorophenyl]oxazolidine-2-one(0.100 g, 0.184 mmol) in 5% TFA and 2.5% triisopropylsilane in DCM (2mL) is stirred at r.t. for 1 h. Solvent is removed under vacuum, and theresidue is dissolved in THF (2 mL). 2-Bromoethanol (0.0196 ml, 0.276mmol) is added followed by triethylamine (0.0513 mL, 0.368 mmol). Thereaction is stirred at r.t. for 2 h, diluted with ethyl acetate, washedwith water, brine, and dried Solvent is removed under vacuum and theresidue is purified by PTLC (10% MeOH in DCM) to give the product.

Example 12

5-(S)-Aminomethyl-3-[4′-(tert-butoxy)carbonyl-3′-fluorophenyl]oxazolidine-2-one

A mixture of triphenylphosphine (0.521 g, 1.99 mmol) and5-(S)-azidomethyl-3-[4′-(tert-butoxy)carbonyl-3′-fluorophenyl]]oxazolidine-2-one(0.607 g, 1.80 mmol) in THF (10 ml) was stirred at r.t. for 2 h. Water(0.259 ml, 14.4 mmol) was added, and the mixture was heated at 40° C.overnight. The reaction mixture was evaporated, the residue taken up inethyl acetate (20 mL) and extracted with 3% aqueous citric acid (3×25ml). Combined aqueous extracts were neutralized with saturated aqueoussodium bicarbonate and then extracted with ethyl acetate. Combinedorganic layers were washed with brine, dried (MgSO₄), ′and evaporated togive the product as a white solid (0.62 g, 99%). MS (m/z): [M+H]⁺=311.

5-(S)-Thioacetamidomethyl-3-[4′-(tert-butoxy)carbonyl-3′-fluorophenyl]oxazo-lidine-2-one

A solution of5-(S)-aminomethyl-3-[4′-(tert-butoxy)carbonyl-3′-fluorophenyl]-oxazolidine-2-one(3.00 g, 9.66 mmol), triethylamine (1.35 ml, 19.3 mmol), and ethyldithioacetate (1.22 ml, 10.6 mmol) in DMF (8 mL) was stirred at roomtemperature for 3 hours. The reaction mixture was diluted with ethylacetate (50 ml), washed with 3% aqueous citric acid (3×30 mL), saturatedaqueous sodium bicarbonate (30 mL), brine, and dried (MgSO₄).Evaporation afforded the product as a white solid (3.00 g, 84%). MS(m/z): [M+H]⁺=369.

Example 13

5-(S)-Thioacetamidomethyl-3-(4′-carboxy-3′-fluorophenyl)oxazolidine-2-one

5-(S)-Thioamidomethyl-3-[4′-(tert-butoxy)carbonyl-3′-fluorophenyl]oxazolidi-ne-2-one(2.50 g, 6.79 mmol) was dissolved in 50% TFA/DCM (30 mL) and stirred for1 h at r.t. Solvents were removed under vacuum to afford the product asa white solid (2.12 g, 99%). M.p. 180-2° C. MS (m/z): [M+H]⁺=313.

Example 14

5-(S)-Thioacetamidomethyl-3-[4′-(thiazole-2″-yl)aminocarbonyl-3′-fluorophenyl]oxazolidine-2-one

A solution of5-(S)-thioacetamidomethyl-3-(4′-carboxy-3′-fluorophenyl)-oxazolidine-2-one(0.037 g, 0.120 mmol), O-(7-azabenzotriazol-1-yl)-N, N, N′,N′-tetramethyluronium hexafluorophosphate (0.0502 g, 0.132 mmol), andDIEA (0.0627 mL, 0.360 mmol) in DMF (0.5 mL) was stirred at r.t. for 20minutes. 2-Aminothiazole (0.0120 mg, 0.120 mmol) was added and themixture stirred overnight. Most of the solvent was removed under vacuumand the residue purified by preparative HPLC to give pure product as awhite solid (0.020 mg, 42%). MS (m/z): [M+H]⁺=395.

Example 15

5-(S)-Thioacetamidomethyl-3-[4′-(thiazole-2″-yl)aminothiocarbonyl-3′-fluorophenyl]oxazolidine-2-one

A mixture of5-(S)-thioacetamidomethyl-3-[4′-(thiazole-2″-yl)aminocarbonyl-3′-fluorophenyl]oxazolidine-2-one(0.040 g, 0.10 mmol) and Lawesson reagent (0.020 g, 0.05 mmol) indioxane (0.5 mL) is stirred at 60-70° C. overnight. Solvent is removedunder vacuum and the crude product is purified by PTLC.

Example 16

5-(S)-Thioacetamidomethyl-3-[4′-(pentafluorophenoxy)carbonyl-3′-fluorophenyl]oxazolidine-2-one

A mixture of5-(S)-thioamidomethyl-3-(4′-carboxy-3′-fluorophenyl)oxazol-idine-2-one(0.650 g, 2.08 mmol), pyridine (0.673 ml, 8.32 mmol), andpentafluorophenyl trifluoroacetate (0.429 ml, 2.50 mmol) in DMF (8 mL)was stirred at r.t. for 3 h. The reaction mixture was diluted with ethylacetate, washed with 3% aqueous citric acid, brine, and dried (MgSO₄).Evaporation afforded the pure product as a white solid (0.90 g, 90%).M.p. 163-4° C.; MS (m/z): [M+H]⁺=479.

Example 17

5-(S)-Thioacetamidomethyl-3-[4′-(N-methylamino)carbonyl-3′-fluorophenyl]-oxazolidine-2-one

A solution of5-(S)-thioacetamidomethyl-3-[4′-(pentafluorophenoxy)carbonyl-3′-fluorophe-nyl]oxazolidine-2-one(0.100 g, 0.209 mmol) in 2 M methylamine in THF (1.0 mL) was stirred atr.t. for 1 h. Solvent was removed under vacuum and the residue purifiedby PTLC (10% MeOH in DCM) to give the pure product as a white solid(0.054 g, 80%). M.p. 176-7° C. MS (m/z): [M+H]⁺=326.

Example 18

5-(S)-Thioacetamidomethyl-3-[4′-methoxycarbonyl-3′-fluorophenyl]oxazoli-dine-2-one

A solution of5-(S)-thioacetamidomethyl-3-[4′-(pentafluorophenoxy)carbonyl-3′-fluorophenyl]oxazolidine-2-one(0.100 g, 0.209 mmol) and 25% sodium methoxide in methanol (0.0573 ml,0.251 mmol) in methanol (2 mL) was stirred at r.t. for 1 h. solvent wasremoved under vacuum and the residue purified by PTLC (10% MeOH in DCM)to give the pure product as a white solid (0.057 g, 84%). M.p. 152-4° C.MS (m/z): [M+H]⁺=327.

Example 19

5-(S)-Thioacetamidomethyl-3-[4′-(imidazole-2″-yl)aminocarbonyl-3′-fluoro-phenyl]-oxazolidine-2-one

A solution of5-(S)-thioacetamidomethyl-3-[4′-(pentafluorophenoxy)carbonyl-3′-fluorophenyl]oxazolidine-2-one(0.162 g, 0.34 mmol) and 2-aminoimidazole (0.083 mg, 1.0 mmol) in THF(5.0 mL) was stirred at r.t. for 0.5 h and then at 45° C. overnight.Solvent was removed under vacuum and the residue purified by PTLC (10%MeOH in DCM) to give the pure product as a white solid (0.058 g, 45%).MS (m/z): [M+H]⁺=378.

Example 20

5-(S)-Thioacetamidomethyl-3-[4′-(imidazole-2″-yl)thioaminocarbonyl-3′-fluorophenyl]-oxazolidine-2-one

A mixture of5-(S)-thioacetamidomethyl-3-[4′-(imidazole-2″-yl)amino-carbonyl-3′-fluorophenyl]oxazolidine-2-one(0.038 g, 0.10 mmol) and Lawesson reagent (0.020 g, 0.05 mmol) indioxane (0.5 mL) is stirred at 60-70° C. overnight. Solvent is removedunder vacuum and the crude product is purified by PTLC.

Example 21

5-(S)-Azidomethyl-3-[4′-(tert-butoxycarbonyl)amino-3′-fluorophenyl]-oxazolidine-2-one

TFA (30 mL) was added to a solution of5-(S)-azidomethyl-3-[4′-(tert-butoxy)carbonyl-3′-fluorophenyl]oxazolidine-2-one(6.72 g, 20 mmol) in DCM (20 mL), and the solution was kept at r.t. for1 h. Solvents were removed under vacuum to afford5-(S)-azidomethyl-3-(4′-carboxy-3′-fluorophenyl)oxazolidine-2-one. THF(75 mL) was added, followed by t-butanol (9.5 mL, 100 mmol),triethylamine (3.6 mL, 26 mmol), and diphenylphosphoryl azide (5.6 mL,26 mmol). The mixture was stirred at r.t. under nitrogen atmosphere for2 h, and then at 70° C. overnight. Solvent was removed under vacuum, andthe residue distributed between ethyl acetate (150 mL) and aq. saturatedsodium bicarbonate (100 mL). Aq. phase was washed with ethyl acetate(2×50 mL). Combined organic layers were washed with aq. saturated sodiumbicarbonate, water, brine, and dried (MgSO₄). Solvent was removed undervacuum, and the product purified by silica gel column chromatography(eluent: DCM). Yield 4.1 g (58%). MS (m/z): [M+H]⁺=352.

5-(S)-Aminomethyl-3-[4′-(tert-butoxycarbonyl)amino-3′-fluorophenyl]-oxazolidine-2-one

A mixture of triphenylphosphine (0.521 g, 1.99 mmol) and5-(S)-azidomethyl-3-[4′-(tert-butoxycarbonyl)amino-3′-fluorophenyl]]oxazolidine-2-one(0.632 g, 1.80 mmol) in THF (10 ml) was stirred at r.t. for 2 h. Water(0.259 ml, 14.4 mmol) was added, and the mixture was heated at 40° C.overnight. The reaction mixture was evaporated, the residue taken up inethyl acetate (20 mL) and extracted with 3% aqueous citric acid (3×25ml). Combined aqueous extracts were neutralized with saturated aqueoussodium bicarbonate and then extracted with ethyl acetate. Combinedorganic layers were washed with brine, dried (MgSO₄), and evaporated togive the product as a white solid (0.53 g, 90%). MS (m/z): [M+H]⁺=326.

5-(S)-Acetamidomethyl-3-[4′-amino-3′-fluorophenyl]oxazolidine-2-one

Acetic anhydride (0.15 mL) was added to a solution of5-(S)-aminomethyl-3-[4′-(tert-butoxycarbonyl)amino-3′-fluorophenyl]oxazolidine-2-one(0.325 g, 1.0 mmol) and pyridine (0.25 mL) in DCM (4.0 mL). The mixturewas stirred at r.t. for 4 h, and solvent was removed under vacuum. Theresulted5-(S)-acetamidomethyl-3-[4′-(tert-butoxycarbonyl)amino-3′-fluorophenyl]oxazoli-dine-2-onewas washed with water (2×3 mL), diethyl ether (3 mL), and dried undervacuum. 50% TFA in DCM (3 ′mL) was added, and the mixture was kept atr.t. for 1 h. Solvents were removed under vacuum, and the residuedistributed between ethyl acetate (40 mL) and saturated aq. sodiumbicarbonate (20 mL). Organic layer was washed with aq. sodiumbicarbonate, water, brine, dried (MgSO₄). Solvent was removed undervacuum to afford the product as a white solid. Yield 0.25 g (95%). MS(m/z): [M+H]⁺=268.

5-(S)-Thioacetamidomethyl-3-[4′-amino-3′-fluorophenyl]oxazolidine-2-one

A mixture of5-(S)-acetamidomethyl-3-[4′-amino-3′-fluorophenyl]oxazoli-dine-2-one.(0.100 g, 0.374 mmol) and Lawesson's reagent (0.151 g, 0.374 mol) indioxane (2 ml) was stirred at 65° C. for 2 h. The solution wasconcentrated under vacuum and the residue purified by PTLC (10%methanol/dichloromethane) to give a tan solid (0.104 g, 98%); mp 137-88°C.; MS: (M+H)⁺=284.

Example 22

5-(S)-Thioacetamidomethyl-3-[4′-acetamido-3′-fluorophenyl]oxazolidine-2-one

A solution of5-(S)-thioacetamidomethyl-3-[4′-amino-3′-fluorophenyl]oxazoli-dine-2-one(0.070 g, 0.247 mmol), acetic anhydride (0.25 mL), pyridine (0.38 mL),and dichloromethane (0.75 mL) was stirred at r.t. for 4 h. Solvent wasremoved under vacuum and the crude product purified by PTLC (10% MeOH inDCM) to give a white solid (0.076 g, 95%). M.p. 200-1° C.; MS (m/z):(M+H)⁺=326.

Example 23

5-(S)-Thioacetamidomethyl-3-[4′-(5″-nitro-2″-furoyl)-3′-fluorophenyl]oxazo-lidine-2-one

5-Nitro-2-furoyl chloride (0.069 g, 0.392 mmol) in THF (1 mL) was addeddropwise to a solution of5-(S)-thioacetamidomethyl-3-[4′-amino-3′-fluorophenyl]oxazolidine-2-one(0.111 g, 0.392 mmol) and triethylamine (0.109 ml, 0.784 mmol) in THF (3mL) at 0° C. The mixture was stirred at r.t. for 1 h. Ethyl acetate wasadded, and the mixture washed with water, saturated aq. sodiumbicarbonate, brine, and dried (MgSO₄). Solvent was removed under vacuum,and the crude material purified by PTLC (10% MeOH in DCM) to gave thepure product as an orange solid (0.079 g, 48%). M.p. 188-8° C. MS (m/z):[M+H]⁺=423.

Example 24

5-(S)-Acetamidomethyl-3-[4′-(1″,2″3″-thiadiazole-4-yl)carbonylamino-3′-fluorophenyl]oxazolidine-2-one

A solution of 1,2,3-thiadiazole-4-carboxylic acid (0.0731 g, 0.562mmol), thionyl chloride (2 ml), and DMF (0.025 ml) was refluxed for 2 h.Solvent was removed under vacuum and the residue dissolved in THF (1mL). Resulted solution was added dropwise at 0° C. to a solution of5-(S)-acetamidomethyl-3-[4′-amino-3′-fluorophenyl]oxazolidine-2-one(0.150 g, 0.562 mmol) and triethylamine (0.157 mL, 1.12 mmol) in THF (3mL), and the mixture stirred for 1 h at r.t. The reaction mixture wasdiluted with ethyl acetate and washed with water, saturated aq. sodiumbicarbonate, brine, and dried (MgSO₄). Evaporation and purification byPTLC (10% MeOH in DCM) gave pure product as a tan solid (0.132 g, 62%);mp 233° C.; MS: (M+H)⁺=380.

Example 25

5-(S)-Thioacetamidomethyl-3-[4′-(1″,2″3″-thiadiazole-4-yl)carbonylamino-3′-fluorophenyl]oxazolidine-2-one

A mixture of5-(S)-acetamidomethyl-3-[4′-(1″,2″3″-thiadiazole-4-yl)carbonyl-amino-3′-fluorophenyl]oxazolidine-2-one.(0.0703 g, 0.185 mmol) and Lawesson's reagent (0.0374 g, 0.0925 mmol) indioxane (3 mL) and sulfolane (0.02 mL) was stirred at 65° C. for 2 h.The solution was concentrated under vacuum, and the residue purified byPTLC (10% MeOH in DCM) to give a white solid (0.037 g, 51%). M.p. 203-4°C. MS (m/z): [M+H]⁺=396.

Example 26

5-(S)-Acetamidomethyl-3-[4′-formamido-3′-fluorophenyl]oxazolidine-2-one

A solution of5-(S)-acetamidomethyl-3-[4′-amino-3′-fluorophenyl]-oxazolidine-2-one(0.200 g, 0.748 mmol), p-nitrophenyl formate (0.188 g, 1.12 mmol), and2,6-di-(tert-butyl)pyridine (0.336 mL, 1.50 mmol) in THF (4 mL) wasstirred at 65° C. overnight. Solvent was removed under vacuum and theresidue purified by PTLC (30% acetone in DCM) to give product as a whitesolid (0.188 g, 85%). M.p. 196-8° C.; MS (m/z): [M+H]⁺=296.

5-(S)-Thioacetamidomethyl-3-[4′-formamido-3′-fluorophenyl]oxazolidine-2-one

Prepared from5-(S)-thiocetamidomethyl-3-[4′-amino-3′-fluorophenyl]oxazo-lidine-2-one(0.100 g, 0.353 mmol) as described above for the synthesis of5-(S)-acet-amidomethyl-3-[4′-formamido-3′-fluorophenyl]oxazolidine-2-one.White solid (0.0979 g, 89%). M.p. 177-8° C. MS (m/z): [M+H]⁺=312.

Example 27

5-(S)-Acetamidomethyl-3-[4′-methylamino-3′-fluorophenyl]oxazolidine-2-one

Methyl iodide (0.86 mL, 13.8 mmol) was added dropwise to the mixture of5-(S)-azidomethyl-3-[4′-(tert-butoxycarbonyl)amino-3′-fluorophenyl]oxazolidine-2-one(1.6 g, 4.6 mmol) and LiH (0.110 g, 13.8 mmol) in dry DMSO (15 mL). Themixture was sonicated for 1 h at r.t., and then stirred overnight. Water(200 mL) and diethyl ether (200 mL) were added, organic layer separatedand aq. phase washed with ether (2×100 mL). Combined organic layers werewashed with water (5×200 mL), brine, dried (MgSO₄). Solvent wasevaporated under vacuum to afford5-(S)-azidomethyl-3-[4′-(tert-butoxycarbonyl)methylamino-3′-fluorophenyl]oxazolidine-2-oneas a thick oil [yield 1.6 g (95%); MS (m/z): [M+H]⁺=366]. Theintermediate was converted into5-(S)-aminomethyl-3-[4′-(tert-butoxycarbonyl)methylamino-3′-fluoro-phenyl]oxazolidine-2-onewith triphenylphosphine (1.25 g, 4.8 mmol) as described above for thesynthesis of5-(S)-aminomethyl-3-[4′-(tert-butoxycarbonyl)methylamino-3′-fluorophenyl]oxazolidine-2-one.The resulted5-(S)-aminomethyl-3-[4′-(tert-butoxycarbonyl)methylamino-3′-fluoro-phenyl]oxazolidine-2-onewas converted into5-(S)-acetamidomethyl-3-[4′-methylamino-3′-fluorophenyl]oxazolidine-2-onevia acetylation with acetic anhydride followed by TFA deprotection asdescribed above for the synthesis of5-(S)-acetamidomethyl-3-[4′-methylamino-3′-fluorophenyl]-oxazolidine-2-one.Yield 1.03 g (80%). R_(t) 3.0 min. MS (m/z): [M+H]⁺=282.

5-(S)-Thioacetamidomethyl-3-[4′-methylamino-3′-fluorophenyl]oxazolidine-2-one

A mixture of5-(S)-acetamidomethyl-3-[4′-methylamino-3′-fluoro-phenyl]oxazolidine-2-one(0.100 g, 0.356 mmol) and Lawesson reagent (0.144 g, 0.356 mmol) indioxane (3 mL) was stirred at 65° C. for 2 h. Solvent was removed undervacuum and the residue purified by PTLC (10% methanol/dichloromethane)to give a product as foam. Yield 0.097 g (92%). MS (m/z): [M+H]⁺=298.

Example 28

5-(S)-Thioacetamidomethyl-3-[4′-(N-methylformamido)-3′-fluorophenyl]oxa-zolidine-2-one

A mixture of5-(S)-thioacetamidomethyl-3-[4′-methylamino-3′-fluorophenyl]-oxazolidine-2-one(0.100 g, 0.337 mmol) with p-nitrophenyl formate (0.084 g, 0.505 mmol),and (2,6-di-tert-butyl)pyridine (0.151 mL, 0.674 mmol) in THF (4 mL) wasstirred at r.t. overnight. Solvent was removed under vacuum and theresidue purified by PTLC (30% acetone in DCM) to give product as a whitesolid (0.089 g, 82%). M.p. 105-7° C. MS (m/z): [M+H]⁺=326.

5-(S)-Acetamidomethyl-3-[4′-(N-methylformamido)-3′-fluorophenyl]oxa-zolidine-2-one

A solution of5-(S)-acetamidomethyl-3-[4′-methylamino-3′-fluorophenyl]oxa-zolidine-2-one(0.200 g, 0.711 mmol), p-nitrophenyl formate (0.178 g, 1.07 mmol), and2,6-di-tert-butylpyridine (0.319 mL, 1.42 mmol) in THF (4 mL) wasstirred at r.t. overnight. Solvent was removed under vacuum and theresidue purified by PTLC (30% acetone/dichloromethane) to give productas a white solid (0.188 g, 85%). M.p. 116-7° C.; MS (m/z): [M+H]⁺=310.

Example 29

5-(S)-Thiocetamidomethyl-3-[4′-(N-methylthioformamido)-3′-fluorophenyl]-oxazolidine-2-one

A mixture of5-(S)-acetamidomethyl-3-[4′-(N-methylformamido)-3′-fluorophenyl]oxazolidine-2-one(0.100 g, 0.323 mmol) and Lawesson reagent (0.131 g, 0.323 mmol) indioxane (3 mL) was stirred at 65° C. for 2 hours. Solvent was removedunder vacuum and the residue purified by PTLC (10% MeOH in DCM) to givea white solid (0.101 g, 92%). M.p. 103-4° C. MS (m/z): [M+H]⁺=342.

Example 30

5-(S)-Acetamidomethyl-3-[4′-(5″,6″-dihydro-1″,4″,2″-dioxazine-3″-yl)-3′-fluorophenyl]oxazolidine-2-one

A solution of5-(S)-acetamidomethyl-3-[4′-(N-hydroxyamino)carbonyl-3′-fluorophenyl]oxazolidine-2-one(0.100 g, 0.321 mmol; prepared as described in U.S. Pat. No.09/235,771), cesium carbonate (0.209 g, 0.643 mmol), and1,2-dibromoethane (0.0415 mL, 0.482 mmol) in 1-methyl-2-pyrrolidinone (4mL) was heated at 100° C. overnight. The reaction mixture was dilutedwith ethyl acetate, washed with water, brine, dried (MgSO₄). Solvent wasremoved under vacuum, and the residue purified by PTLC (10% MeOH in DCM)to give product as a white solid (0.052 g, 48%). M.p. 203-4° C. MS(m/z): [M+H]⁺=338.

5-(S)-Thioacetamidomethyl-3-[4′-(5″,6″-dihydro-1″,4″,2″-dioxazine-3″-yl)-3′-fluorophenyl]oxazolidine-2-one

A mixture of5-(S)-acetamidomethyl-3-[4′-(5″,6″-dihydro-1″,4″,2″-dioxazine-3″-yl)-3′-fluorophenyl]oxazolidine-2-one(0.040 g, 0.119 mmol) and Lawesson's reagent (0.0481 g, 0.119 mmol) indioxane (2 mL) was stirred at 65° C. for 2 hours. solvent was removedunder vacuum and the residue purified by PTLC 10% MeOH in DCM) to giveproduct as a white solid (0.034 g, 81%). M.p. 166-7° C.; MS (m/z):[M+H]⁺=354.

Example 31

5-(S)-Thioacetamidomethyl-3-[4′-[N-methyl-(N-methylsulfonyl)amino]-3′-fluorophenyl]oxazolidine-2-one

A mixture of5-(S)-acetamidomethyl-3-[4′-[N-methyl-(N-methylsulfonyl)-amino]-3′-fluorophenyl]oxazolidine-2-one(0.100 g, 0.279 mmol; prepared analogously to U.S. Pat. No. 09/235,771)and Lawesson's reagent (0.113 g, 0.279 mmol) in dioxane (3 mL) wasstirred and heated at 65° C. for 2 h. Solvent was removed under vacuumand the residue purified by PTLC (10% MeOH-DCM) to give a foam (0.090 g,80%). MS (m/z): [M+H]⁺=376.

Example 32

Preparation and Use of Polymeric Thioacylating Agents

Polymeric Thioacylating Reagent: Merrifield Resin Dithioacetate

Carbon disulfide (0.725 mL, 0.0121 mol) was added dropwise with stirringat r.t. to a solution of 3.0 M of methylmagnesium bromide in ether (3.09mL, 9.27 mmol) in THF (15 mL), and the mixture stirred for 3 h undernitrogen atmosphere. Merrifield resin (0.74 mmol/g, 2.5 g, 1.85 mmol)was added in one portion, and the reaction agitated overnight. The resinwas filtered, washed liberally with THF, MeOH, DCM, and dried undervacuum.

Thioamidation Using Merrifield Resin Dithioacetate

Merrifield resin dithioacetate (0.458 g, 0.339 mmol) and5-(S)-aminomethyl-3-(4′-morpholino-3′-fluorophenyl)oxazolidine-2-one(0.020 g, 0.0677 mmol) in DMF (2 ml) were agitated at 65° C. for 4hours. Supernatant was filtered off and the solvent removed under vacuumto afford5-(S)-thioamidomethyl-3-(4′-morpholino-3′-fluorophenyl)oxazolidine-2-one.MS (m/z): [M+H]⁺=354.

Example 33

Solid Phase Thioamide Synthesis

A mixture of5-(S)-aminomethyl-3-(4′-morpholino-3′-fluorophenyl)-oxazolidine-2-oneimmobilized on BAL-linker functionalized Tentagel polymer (0.21 g, 0.06mmol) and Lawesson reagent (0.088 g, 0.217 mmol) in dioxane (3 mL) wasagitated at 60° C. for 3 h. The resin was filtered, washed liberallywith DMF, DMSO, DCM, MeOH, and dried under vacuum. 40% TFA in DCM (2 mL)added, and the mixture agitated for 1 h at r.t. Supernatant was filteredoff, and solvents removed under vacuum to afford5-(S)-thioamidomethyl-3-(4′-morpholino-3′-fluorophenyl)oxazolidine-2-one.Rt 3.8 min. MS (m/z): [M+H]⁺=354.

Example 34

5-(S)-Azidomethyl-3-[4′-(5″-amino-1″,3″,4″-thiadiazole-2″-yl)-3′-fluoro-phenyl]oxazolidine-2-one

60% TFA in DCM (5 mL) was added to5-(S)-azidomethyl-3-[4′-tert-butoxycarbonyl-3′-fluorophenyl]oxazolidine-2-one(0.336 g, 1 mmol), and the solution kept at r.t. for 1 h. Solvents wereremoved in vacuo to afford5-(S)-azidomethyl-3-[4′-carboxy-3′-fluorophenyl]oxazolidine-2-one (0.280g, 99%). A mixture of5-(S)-azidomethyl-3-[4′-carboxy-3′-fluorophenyl]oxazolidine-2-one wellstirred mixture of (0.080 g, 0.286 mmol) and thiosemicarbazide (0.0957g, 0.286 mmol) in dioxane (2 mL) was heated until the mixture washomogeneous. Phosphorous oxychloride (0.027 ml, 0.29 mmol) was added,and the mixture heated at reflux for 1 h. The mixture was allowed tocool to r.t., and the white precipitate filtered, washed with dioxane,suspended in saturated aqueous sodium bicarbonate, and extracted withethyl acetate. Combined organic extracts were washed with brine, anddried (MgSO₄) Solvent was removed under vacuum, and the crude productpurified by PTLC (10% MeOH in DCM) to give product as a white solid(0.038 g, 40%); MS (m/z): [M+H]⁺=336.

5-(S)-Aminomethyl-3-[4′-(5″-formamido-1″,3″,4″-thiadiazole-2″-yl)-3′-fluoro-phenyl]oxazolidine-2-one

5-(S)-Azidomethyl-3-[4′-(5″-amino-1″,3″,4″-thiadiazole-2″-yl)aminocarbonyl-3′-fluorophenyl]oxazolidine-2-one(0.335 g, 1.0 mmol), p-nitrophenyl formate (0.188 g, 1.12 mmol), and2,6-di-(tert-butyl)pyridine (0.336 mL, 1.50 mmol) in THF (4 mL) isstirred at 50-65° C. overnight. Solvent is removed under vacuum, and theresulted5-(S)-azidomethyl-3-[4′-(5″-formamido-1″,3″,4″-thiadiazole-2″-yl)aminocarbonyl-3′-fluorophenyl]oxazolidine-2-oneintermediate is purified by PTLC (MeOH-DCM). A mixture of5-(S)-azidomethyl-3-[4′-(5″-formamido-1″,3″,4″-thiadiazole-2″-yl)aminocarbonyl-3′-fluorophenyl]oxazolidine-2-one(0.363 g, 1 mmol) and triphenylphosphine (0.262 g, 1.0 mmol) in THF (ca.10 mL) is stirred at r.t. for 3-4 h and then at 40° C. for 2 h. Water(0.5 mL) is added, and the mixture stirred at 40° C. overnight. Solventsare removed in vacuo, and the crude product purified by PTLC (MeOH-DCM).

5-(S)-Acetamidomethyl-3-[4′-(5″-formamido-1″,3″,4″-thiadiazole-2″-yl)-3′-fluorophenyl]oxazolidine-2-one

Acetic anhydride (0.14 mL, 1.5 mmol) is added to5-(S)-aminomethyl-3-[4′-(5″-formamido-1″,3″,4″-thiadiazole-2″-yl)-3′-fluoro-phenyl]oxazolidine-2-one(0.34 g, 1 mmol) and polyvinylpyridine (0.50 g) in THF (7 mL), and themixture is agitated at r.t. for 4 h. Supernatant is collected byfiltration, and the resin washed with excess TBF. Solvent is removedunder vacuum to afford the product which can be further purified by PTLC(MeOH-DCM).

5-(S)-Thioacetamidomethyl-3-[4′-(5″-thioformamido-1″,3″,4″-thiadiazole-2″-yl)-3′-fluorophenyl]oxazolidine-2-one

5-(S)-Acetamidomethyl-3-[4′-(5″-formamido-1″,3″,4″-thiadiazole-2″-yl)-3′-fluoro-phenyl]oxazolidine-2-one(0.38 g, 1.0 mmol) and Lawesson reagent (0.40 g, 1.0 mmol) in dioxane(10 mL) is stirred at 50-65° C. for 4-6 h. Solvent is removed undervacuum and the residue purified by PTLC (MeOH-DCM).

Example 35

5-(S)-Azidomethyl-3-[4′-(5″-methylamino-1″,3″,4″-thiadiazole-2″-yl)-3′-fluoro-phenyl]oxazolidine-2-one

The compound is prepared analogously to described above synthesis of5-(S)-azidomethyl-3-[4′-(5″-amino-1″,3″,4″-thiadiazole-2″-yl)-3′-fluorophenyl]oxazolidine-2-onefrom 5-(S)-azidomethyl-3-[4′-carboxy-3′-fluorophenyl]oxazolidine-2-one(0.10 g, 0.36 mmol), 4-methyl-3-thiosemicarbazide (0.038, 0.36 mmol),and phosphorus oxychloride ((0.033 mL, 0.36 mmol) in dioxane (2 mL).Crude product is purified by PTLC (MeOH-DCM).

5-(S)-Thioacetamidomethyl-3-[4′-(5″-(N-methyl)thioformamido-1″,3″,4″-thiadiazole-2″-yl)-3′-fluorophenyl]oxazolidine-2-one

The compound is prepared from5-(S)-azidomethyl-3-[4′-(5″-methylamino-1″,3″,4″-thiadiazole-2″-yl)-3′-fluorophenyl]oxazolidine-2-oneanalogously to described above synthesis of5-(S)-thioacetamidomethyl-3-[4′-(5″-thioformamido-1″,3″,4″-thiadiazole-2″-yl)-3′-fluorophenyl]oxazolidine-2-onefrom5-(S)-azidomethyl-3-[4′-(5″-amino-1″,3″,4″-thiadiazole-2″-yl)-3′-fluorophenyl]oxazolidine-2-one.Crude product is purified by PTLC (MeOH-DCM).

Example 36

5-(S)-Azidomethyl-3-[4′-(4″-methyl-5″-methylamino-4″,5″-dihydro-1″,3″,4″-thiadiazole-2″-yl)-3′-fluorophenyl]oxazolidine-2-one

A mixture of5-(S)-azidomethyl-3-[4′-(5″-methylamino-1″,3″,4″-thiadiazole-2″-yl)-3′-fluorophenyl]oxazolidine-2-one(0.10 g, 0.29 mmol) and methyl iodide (0.036 mL, 0.57 mmol) in dioxane(ca. 2 mL) is stirred under reflux overnight. Solvent is removed undervacuum, and the crude product is purified by PTLC (MeOH-DCM).

5-(S)-Aminomethyl-3-[4′-(4″-methyl-5″-methylimino-4″,5″-dihydro-1″,3″,4″-thiadiazole-2″-yl)-3′-fluorophenyl]oxazolidine-2-one

A mixture of5-(S)-azidomethyl-3-[4′-(4″-methyl-5″-methylimino-4″,5″-dihydro-1″,3″,4″-thiadiazole-2″-yl)-3′-fluorophenyl]oxazolidine-2-one(1.0 mmol) and triphenylphosphine (0.262 g, 1.0 mmol) in THF (ca. 10 mL)is stirred at r.t. for 3-4 h and then at 40° C. for 2 h. Water (0.5 mL)is added, and the mixture stirred at 40° C. overnight. Solvent isremoved in vacuo, and the crude product purified by PTLC (MeOH-DCM).

5-(S)-Thioacetamidomethyl-3-[4′-(4″-methyl-5″-methylimino-4″,5″-dihydro-1″,3″,4″-thiadiazole-2″-yl)-3′-fluorophenyl]oxazolidine-2-one

5-(S)-Aminomethyl-3-[4′-(4″-methyl-5″-methylimino-4″,5″-dihydro-1″,3″,4″-thiadiazole-2″-yl)-3′-fluorophenyl]oxazolidine-2-one(1.0 mmol) and ethyl dithioacetate (0.130 ml, 1.13 mmol) withtriethylamine (0.215 ml,1.54 mmol) in DCM is stirred at r.t. overnight.The reaction mixture is concentrated under vacuum and the residuepurified by PTLC (MeOH-DCM).

Example 37

Protocol for Assay of Antimicrobial Activity

Minimum inhibitor concentrations (MICs) were determined using themicrodilution method according to National Committee for ClinicalLaboratory Standards (NCCLS) procedures. Compounds were suspended inDMSO at 10 mg/ml and stored at −20° C. The range of concentrationstested was 64-0.06 μg/ml using two-fold dilutions.

To prepare the inoculum, bacterial cultures were grown overnight at 35°C. on agar plates and each organism was resuspended in 1 ml saline toobtain a 0.5 McFarlands density standard. This was subsequently diluted1:200 into Mueller-Hinton Broth (MHB) or Haemophilus Test Medium (HTM;for Haemophilus) providing a final inoculum size of 5*10⁵ cfu/ml. Afterinoculation with the bacteria, assay plates were incubated at 35° C. for18-24 h. The MIC was defined as the lowest concentration of compoundthat did not produce visible growth after incubation. Gram positive andgram negative strains used included Staphylococcus aureus, Enterococcusfaecium, Enterococcus faecalis, Streptococcus pneumoniae, Haemophilusinfluenzae, Pseudomonas aeruginosa, Escherichia coli, and E. coli(acr)—an efflux pump mutant.

Example 38

5-(S)-Azidomethyl-3-[4′-aminocarbonyl-3′-fluorophenyl]oxazolidine-2-one

A solution of5-(S)-azidomethyl-3-[4′-carboxy-3′-fluorophenyl-]oxazolidine-2-one (3.2g, 11.4 mmol; prepared as described in Example 3),O-(7-azabenzotriazol-1-yl)-N,N,N′,N′,-tetramethyluroniumhexafluorophosphate (6.5 g, 17.1 mmole) and N,N′-diisopropylethylamine(5.9 g, 7.9 ml , 45.6 mmol) in DMF (12 ml) was stirred at roomtemperature for 20 min. Ammonium chloride (1.2 g, 22.8 mmol) was added,and the reaction mixture was stirred at r. t. overnight. Most of thesolvent was removed under vacuum, and the residue taken up in ethylacetate and washed twice with 3% aq. citric acid and brine. Organiclayer was dried (Na₂SO₄) and concentrated under vacuum. Crude materialwas purified by silica gel chromatography eluting with 15% methanol inethyl acetate to afford a white crystalline product (2.8 g, 91%). HPLCR_(t)=4.7, MS (m/z): [M+H]⁺=280.

5-(S)-Aminomethyl-3-[4′-aminocarbonyl -3′-fluorophenyl]oxazolidine-2-one

Triphenylphosphine (2.9 g, 11.0 mmol) was added portionwise to asolution of5-(S)-azidomethyl-3-[4′-aminocarbonyl-3′-fluorophenyl]oxazolidine-2-one(2.8 g, 10.0 mmol) in THF (75 ml) under nitrogen atmosphere. Thesolution was stirred at 40° C. for 2 h, water (2.0 ml) added, and thereaction mixture was stirred at 40° C. overnight. Solvent was removedunder vacuum, and the resulting solid was triturated with ether.Precipitated material was filtered, washed with ether and ethanol anddried under vacuum to afford the product as white crystals (1.7 g, 69%).HPLC R_(t)=5.0 min. MS (m/z): [M+H]⁺=254.

5-(S)-Thioacetamidomethyl-3-[4′-aminocarbonyl-3′-fluorophenyl]oxazolidine-2-one

A solution of5-(S)-aminomethyl-3-[4′-aminocarbonyl-3′-fluorophenyl]oxazolidine-2-one(1.75 g, 6.9 mmol), triethylamine (2.0 ml, 13.8 mmol) and ethyldithioacetate (0.87 ml, 7.6 mmol) and DMF (5 ml) in acetonitrile (5 ml)was stirred at r.t. for 48 h. Solvent was removed under vacuum, and thecrude material purified by silica gel chromatography (eluent: 10%methanol in ethyl acetate). White crystalline solid (1.3 g, 61%). HPLCR_(t)=4.5 min. MS (m/z): [M+H]⁺=312.

Example 39

5-(S)-Azidomethyl-3-[4′-(pentafluorophenoxy)carbonyl-3′-fluorophenyl]-oxazolidine-2-one

Pentafluorophenyl trifluoroacetate (2.2 ml, 12.9 mmol) was addeddropwise with stirring to a solution of5-(S)-azidomethyl-3-[4′-carboxy-3′-fluorophenyl]oxazolidine-2-one (3.0g, 10.7 mmol; prepared as described in Example 3) and pyridine (3.5 ml,42.8 mmol) in DMF (10 ml). The mixture was stirred at r.t. for 2.5 h,and ethyl acetate with 3% aq. citric acid added. Organic layer waswashed twice with 3% citric acid, brine, and dried (Na₂SO₄). The crudematerial was washed with ether-hexanes to afford a white crystallineproduct (4.3 g, 90%). HPLC R_(t)=7.1. MS (m/z): [M+H]⁺=447.

5-(S)-Azidomethyl-3-[4′-(N-methoxyamino)carbonyl-3′-fluorophenyl]-oxazolidine-2-one

N-Methoxyamine hydrochloride (123 mg, 1.5 mmol) was added to a solutionof5-(S)-azidomethyl-3-[4′-(pentafluorophenoxy)carbonyl-3′-fluorophenyl]-oxazolidine-2-one(600 mg, 1.3 mmol) and diisopropylethylamine (0.26 ml, 1.5 mmol) in THF(8 ml), and the mixture stirred overnight at r.t. Solvent was removedunder vacuum, and ethyl acetate with 3% aq. citric acid added. Organiclayer was washed twice with 3% citric acid, brine, and dried (Na₂SO₄).Solvent was removed under vacuum, and the crude material crystallizedfrom ethanol-ether to give a white crystalline product (335 mg, 83%).HPLC R_(t)=4.8. MS (m/z): [M+H]⁺=310.

5-(S)-Aminomethyl-3-[4′-(N-methoxyamino)carbonyl-3′-fluorophenyl]-oxazolidine-2-one

Triphenylphosphine (317 mg, 1.2 mmol) was added to a solution of5-(S)-azidomethyl-3-[4′-(N-methoxyamino)carbonyl-3′-fluorophenyl]-oxazolidine-2-one.(0.335 g, 1.1 mmol) in THF (8 ml) under nitrogen atmosphere. Thesolution was stirred at 40° C. for 2 h, water (0.24 ml) was added, andthe reaction mixture stirred at 40° C. overnight. Solvent was removedunder vacuum, and the resulting solid was triturated with ether.Precipitated material was filtered, washed with ether and ethanol anddried under vacuum to afford the product as white crystals (120 mg,42%). HPLC R_(t)=3.5 min. MS (m/z): [M+H]⁺=284.

5-(S)-Thioacetamidomethyl-3-[4′-(N-hydroxyamino)carbonyl-3′-fluorophenyl]-oxazolidine-2-one

A solution of5-(S)-aminomethyl-3-[4′-(N-methoxyamino)carbonyl-3′-fluorophenyl]-oxazolidine-2-one(0.053 ml, 0.47 mmol), triethylamine (0.12 ml, 0.84 mmol) and ethyldithioacetate (0.87 ml, 7.6 mmol) in DMF (0.75 ml) was stirred at r.t.for 48 h. Solvent was removed under vacuum, and the crude materialpurified by silica gel PTLC (eluent: 5% MeOH in ethyl acetate). Whitecrystalline solid (100 mg, 70%). HPLC R_(t)=4.6 min. MS (m/z):[M+H]⁺=342.

Example 40

5-(S)-Acetamidomethyl-3-[4′-(N,N-dimethylamino)carbonyl-3′-fluorophenyl]-oxazolidine-2-one

A mixture of5-(S)-thioacetamidomethyl-3-(4′-carboxy-3′-fluorophenyl)oxazolidine-2-one(0.33 g, 1.06 mmol; prepared as described in Example 13),O-(7-azabenzotriazol-1-yl)-N, N, N′, N′,-tetramethyluroniumhexafluorophosphate (0.428 g, 1.1 mmole) and N,N′-diisopropylethylamine(0.38 ml, 2.1 mmol) in DMF (1.5 ml) was stirred at r.t. for 20 min.Dimethylamine hydrochloride (96 mg, 1.2 mmole) was added, and themixture stirred at r.t. overnight. Solvent was removed under vacuum, andthe product purified by by silica gel PTLC (eluent: 10% MeOH in ethylacetate). White crystals (117 mg, 33%). HPLC R_(t)=4.2. MS (m/z):[M+H]⁺=340.

Example 41

5-(S)-Acetamidomethyl-3-[4′-(Pentafluorophenoxy)carbonyl-3′-fluorophenyl]-oxazolidine-2-one

60% TFA in dichloroethane (10 ml) was added to5-(S)-azidomethyl-3-[4′-tert-butoxycarbonyl-3′-fluorophenyl]oxazolidine-2-one(2.00 g, 5.95 mmol; prepared as described for Example 2) and thesolution kept at r.t. for 1 h. Solvent was removed under vacuum toafford 5-(S)-azidomethyl-3-[4′-carboxy-3′-fluorophenyl]oxazolidine-2-one(1.65 g, 5.89 mmol, 99%). This intermediate was dissolved in DMF (15ml), and pentafluorophenyl trifluoroacetate (1.21 ml, 7.06 mmol) andpyridine (1.91 ml, 23.6 mmol) were added with stirring. The mixture wasstirred at r.t. for 3 h, most of the solvent removed under vacuum, andthe residue triturated with water. The resulting precipitate wasfiltered, washed with water, ether, and dried under vacuum. Whitecrystals. Yield g (2.53 g, 93%). MS (m/z): [M+H]⁺=463.

5-(S)-Acetamidomethyl-3-[4′-(hydrazino)carbonyl-3′-fluorophenyl]oxazolidine-2-one

Hydrazine (0.041 ml, 1.30 mmol) was added dropwise with stirring to asolution of5-(S)-acetamidomethyl-3-[4′-(pentafluorophenoxy)carbonyl-3′-fluorophenyl]oxazolidine-2-one(0.500 g, 1.08 mmol) in tetrahydrofuran (3 ml). The mixture was stirredat r.t. for 2 h, and the heavy white precipitate filtered, washed withether, and dried under vacuum. Yield 0.295 g (88%). MS (m/z):[M+H]⁺=311.

5-(S)-Thioacetamidomethyl-3-[4′-(hydrazino)carbonyl-3′-fluorophenyl]oxazolidine-2-one

Tetrahydrofuran (5 ml) was added to a mixture of phosphorouspentasulfide (0.143 g, 0.322 mmol) and sodium carbonate (0.0341 g, 0.322mmol) under a nitrogen atmosphere, and the mixture stirred vigorously atr.t. until a clear yellow solution was obtained.5-(S)-Acetamidomethyl-3-[4′-(hydrazino)carbonyl-3′-fluorophenyl]oxazolidine-one(0.100 g, 0.322 mmol) was added in one portion, and the reaction stirredat r.t. overnight. Solvent was removed under vacuum, and the residuepurified by PTLC (10% methanol in DCM) to give the pure product as awhite solid (0.037 g, 35%). M.p. 177° C. MS (m/z): [M+H]⁺=327.

Example 42

5-(S)-Acetamidomethyl-3-[4′-(N-hydroxyamidino)-3′-fluorophenyl]oxazolidine-2-one

O-Trimethylsilylhydroxylamine (0.37 ml, 3.0 mmol) and5-(S)-acetamidomethyl-3-[4′-cyano-3′-fluorophenyl]oxazolidine-2-one(0.277 g, 1.0 mmol) in ethanol (3.0 ml) were stirred at 80° C. in asealed reaction vial for 2.5 h. The mixture was left at r.t. for 48 h,and the crystallized product filtered, rinsed with ethanol (ca. 0.75ml), washed with ether, and dried under vacuum. Yellow crystals. Yield0.260 g (84%). HPLC: R_(t) 2.6 min. MS (m/z): [M+H]⁺=311.

5-(S)-Thioacetamidomethyl-3-[4′-(N-hydroxyamidino)-3′-fluorophenyl]oxazolidine-2-one

The compound is made analogously to that described above for Example 42from5-(S)-acetamidomethyl-3-[4′-(N-hydroxyamidino)-3′-fluorophenyl]oxazolidine-2-one(0.100 g, 0.32 mmol), phosphorous pentasulfide (0.143 g, 0.322 mmol) andsodium carbonate (0.0341 g, 0.322 mmol). The reaction is performed atr.t. overnight. Solvent is removed under vacuum, and the productisolated by preparative reverse phase HPLC.

Example 43

5-(S)-Acetamidomethyl-3-[4′-(N-methoxyamidino)-3′-fluorophenyl]oxazolidine-2-one

Iodomethane (0.02 ml, 0.39 mmol) was added to a solution of5-(S)-acetamidomethyl-3-[4′-(N-hydroxyamidino)-3′-fluorophenyl]oxazolidine-2-one(0.080 g, 0.26 mmol) and tert-butyl-1,1,3,3-tetramethylguanidine (0.058ml, 0.39 mmol) in DMF (1.0 ml), and the mixture was stirred at r.t.overnight. Solvent was removed under vacuum, and the crude productpurified by silica gel PTLC (10% methanol in DCM). HPLC: R_(t) 3.6 min.MS (m/z): [M+H]⁺=325.

5-(S)-Thioacetamidomethyl-3-[4′-(N-methoxyamidino)-3′-fluorophenyl]oxazolidine-2-one

The compound is made analogously to that described above for Example 42from5-(S)-acetamidomethyl-3-[4′-(N-methoxyamidino)-3′-fluorophenyl]oxazolidine-2-one,phosphorous pentasulfide, and sodium carbonate in THF. The reaction isperformed at r.t. overnight. Solvent is removed under vacuum, and theproduct isolated by preparative reverse phase HPLC.

Example 44

5-(S)-Acetamidomethyl-3-[4′-(N,N,N-trimethylaminimido)carbonyl-3′-fluorophenyl]-oxazolidine-2-one

LiH (0.008 g, 1.1 mmol) was added to a solution of5-(S)-acetamidomethyl-3-[4′-(hydrazino)carbonyl-3′-fluorophenyl]oxazolidine-2-one(0.018 g, 0.058 mmol) and methyl iodide (0.062 ml, 1.0 mmol) in dry DMSO(0.50 ml), and the mixture was stirred at r.t. overnight. The reactionwas quenched with methanol (1.0 ml) and water (1.0 ml), and the productwas purified by preparative reverse phase HPLC (gradient from 100% of0.1% aq. TFA (solvent A) to 60% 0.1% TFA in acetonitrile—40% of solventA over 40 min). White solid. Yield 0.005 g (25%). HPLC: R_(t) 2.9 min.MS (m/z): [M+H]⁺=353.

5-(S)-Thioacetamidomethyl-3-[4′-(N,N,N-trimethylaminimido)carbonyl-3′-fluorophenyl]-oxazolidine-2-one

The compound is made analogously to that described above for Example 42from5-(S)-acetamidomethyl-3-[4′-(N,N,N-trimethylaminimido)carbonyl-3′-fluorophenyl]oxazoli-dine-2-one,phosphorous pentasulfide and sodium carbonate in THF. The reaction isperformed at r.t. overnight. Solvent is removed under vacuum, and theproduct isolated by preparative reverse phase HPLC.

Example 45

5-(S)-Thioacetamidomethyl-3-[4′-(6″-methylsulfinylpyridine-3″-yl)aminocarbonyl-3′-fluorophenyl]oxazolidine-2-one

A solution of5-(S)-thioacetamidomethyl-3-[4′-(pentafluorophenoxy)carbonyl-3′-fluorophenyl]oxazolidine-2-one(0.478 g, 1.0 mmol; prepared as described for Example 16),3-amino-6-methylsulfinylpyridine (0.156 g, 1.0 mmol), triethylamine(0.202 g, 2.0 mmol) and 4-dimethylaminopyridine (0.012 g, 0.1 mmol) indry acetonitrile is agitated at 50-60° C. overnight. Volatiles areremoved under vacuum, and the crude product purified by PTLC (eluent:methanol-DCM).

Example 46

5-(S)-Thioacetamidomethyl-3-[4′-(5″-methylsulfinylthiazole-2″-yl)aminocarbonyl-3′-fluorophenyl]oxazolidine-2-one

A solution of5-(S)-thioacetamidomethyl-3-[4′-(pentafluorophenoxy)carbonyl-3′-fluorophenyl]oxazolidine-2-one(0.478 g, 1.0 mmol; prepared as described for Example 16),2-amino-5-methylsulfinylthiazole (0.162 g, 1.0 mmol), triethylamine(0.202 g, 2.0 mmol) and 4-dimethylaminopyridine (0.012 g, 0.1 mmol) indry acetonitrile is agitated at 50-60° C. overnight. Volatiles areremoved under vacuum, and the product purified by PTLC (eluent:methanol-DCM).

Example 47

5-(S)-Thioacetamidomethyl-3-[4′-(5″-methylsulfinyl-1″,3″,4″-thiadiazole-2″-yl)amino-carbonyl-3′-fluorophenyl]oxazolidine-2-one

A solution of5-(S)-thioacetamidomethyl-3-[4′-(pentafluorophenoxy)carbonyl-3′-fluorophenyl]oxazolidine-2-one(0.478 g, 1.0 mmol; prepared as described for Example 16),2-amino-5-methylsulfinylthiazole (0.163 g, 1.0 mmol), triethylamine(0.202 g, 2.0 mmol) and 4-dimethylaminopyridine (0.012 g, 0.1 mmol) indry acetonitrile is agitated at 50-60° C. overnight. Volatiles areremoved under vacuum, and the product purified by PTLC (eluent:methanol-DCM).

Example 48

5-(S)-Acetamidomethyl-3-[4′-(3″-ethoxycarbonyl)thioureido-1″-yl)-3′-fluorophenyl]-oxazolidine-2-one

Ethoxycarbonyl isothiocyanate (0.50 ml, 4.1 mmol) was added to asolution of5-(S)-acetamidomethyl-3-[4′-amino-3′-fluorophenyl]oxazolidine-2-one(0.50 g, 1.87 mmol; prepared as described for Example 21) in a mixtureof NMP and DCM (1:1; 7 ml). Reaction was stirred at r.t. for 3 h, andthe solvent was removed under vacuum. The residue was triturated withexcess of hexanes and then ether. Resulted precipitate was filtered,washed with ether and dried under vaccum. Yield 0.73 g (98%). HPLC R_(t)4.2 min. MS (m/z):[M+H]⁺=399.

5-(S)-Thioacetamidomethyl-3-[4′-(3″-ethoxycarbonyl)thioureido-1″-yl)-3′-fluorophenyl]-oxazolidine-2-one

A mixture of5-(S)-acetamidomethyl-3-[4′-(3″-ethoxycarbonyl)thioureido-1″-yl)-3′-fluorophenyl]-oxazolidine-2-one(0.200 g, 0.50 mmol) and the Lawesson's reagent (0.155 g, 0.38 mmol) in1,4-dioxane (6 ml) was stirred at 65° C. overnight. Solvent was removedunder vacuum, and the crude product purified by silica gel PTLC (eluent:10% acetone in DCM). White solid. Yield 0.124 g (60%). HPLC R_(t) 4.7min. MS (m/z):[M+H]⁺=415.

Example 49

5-(S)-Acetamidomethyl-3-[4′-(3″-ethoxycarbonyl)ureido-1″-yl)-3′-fluorophenyl]-oxazolidine-2-one

Ethoxycarbonyl isocyanate (0.29 ml, 2.8 mmol) was added to a solution of5-(S)-acetamidomethyl-3-[4′-amino-3′-fluorophenyl]oxazolidine-2-one(0.50 g, 1.87 mmol; prepared as described for Example 21) in a mixtureof NMP and DCM (1:1; 7 ml). Reaction was stirred at r.t. for 3 h, andthe solvent was removed under vacuum. The residue was triturated withexcess of hexanes and then ether. Resulted precipitate was filtered,washed with ether and dried under vaccum. Yield 0.65 g (91%). HPLC R_(t)4.0 min. MS (m/z):[M+H]⁺=383.

5-(S)-Thioacetamidomethyl-3-[4′-(3″-ethoxycarbonyl)ureido-1″-yl)-3′-fluorophenyl]-oxazolidine-2-one

A mixture of5-(S)-acetamidomethyl-3-[4′-(3″-ethoxycarbonyl)ureido-1″-yl)-3′-fluorophenyl]oxazolidine-2-one(0.300 g, 0.79 mmol) and the Lawesson's reagent (0.32, 0.79 mmol) in1,4-dioxane (6 ml) was stirred at 65° C. overnight. Precipitated productwas filtered, washed with 1,4-dioxane, ether, and dried under vacuum.White solid. Yield 0.299 g (95%). HPLC R_(t) 4.5 min. MS(m/z):[M+H]⁺=399.

Example 50

5-(S)-Acetamidomethyl-3-[4′-(3″-methoxycarbonyl)thioureido-1″-yl)-3′-fluorophenyl]-oxazolidine-2-one

A solution of5-(S)-acetamidomethyl-3-[4′-amino-3′-fluorophenyl]oxazolidine-2-one(0.50 g, 1.87 mmol; prepared as described for Example 21) in NMP (2 ml)was added dropwise with stirring to a solution of methoxycarbonylisothiocyanate (generated in situ from methyl chloroformate (0.300 ml,3.8 mmol) and Bu₄NCS (1.25 g, 4.16 mmol) in acetonitrile (8 ml), r.t., 6h under nitrogen atmosphere), and the mixture was stirred at r.t.overnight. Solvents were removed under vacuum, the residue dissolved ina mixture of MeOH and DCM (1:1, 30 ml), and stirred with excess of thecation exchange resin IR 120 Plus overnight. Supernatant was filtered,solvents removed under vacuum, and the crude product purified by silicagel PTLC (eluent: 30% acetone in DCM). Yield 0.359 g (50%). HPLC R_(t)3.9 min. MS (m/z):[M+H]⁺=385.

Example 51

5-(S)-Thioacetamidomethyl-3-[4′-(3″-methoxycarbonyl)thioureido-1″-yl)-3′-fluorophenyl]-oxazolidine-2-one

A mixture of5-(S)-acetamidomethyl-3-[4′-(3″-methoxycarbonyl)thioureido-1″-yl)-3′-fluorophenyl]oxazolidine-2-one(0.24 g, 0.63 mmol) and the Lawesson's reagent (0.24, 0.60 mmol) in1,4-dioxane (6 ml) was stirred at 70° C. overnight. Solvent was removedunder vacuum, and the crude product purified by silica gel PTLC (eluent:hexanes-EtOAc 1:1). Yield 0.359 g (80%). HPLC R_(t) 4.4 min. MS(m/z):[M+H]⁺=401.

Example 52

5-(S)-Acetamidomethyl-3-[4′-(3″-methoxycarbonyl)ureido-1″-yl)-3′-fluorophenyl]-oxazolidine-2-one

Methoxycarbonyl isocyanate (0.20 ml, 2.47 mmol) was added to a solutionof 5-(S)-acetamidomethyl-3-[4′-amino-3′-fluorophenyl]oxazolidine-2-one(0.525 g, 1.96 mmol; prepared as described for Example 21) in a mixtureof NMP and DCM (1:1; 10 ml). Reaction was stirred at r.t. for 4 h. Theprecipitated product was filtered, washed with excess of hexanes andether, and dried under vacuum. White solid, yield 0.541 g (75%). HPLCR_(t) 3.7 min. MS (m/z):[M+H]⁺=369.

5-(S)-′Thioacetamidomethyl-3-[4′-(3″-methoxycarbonyl)ureido-1″-yl)-3′-fluorophenyl]-oxazolidine-2-one

A mixture of5-(S)-acetamidomethyl-3-[4′-(3″-methoxycarbonyl)ureido-1″-yl)-3′-fluorophenyl]oxazolidine-2-one(0.291 g, 0.79 mmol) and the Lawesson's reagent (0.32, 0.79 mmol) in1,4-dioxane (6 ml) was stirred at 70° C. overnight. Precipitated productwas filtered, washed with 1,4-dioxane, ether, and dried under vacuum.White solid. Yield 0.212 g (70%). HPLC R_(t) 4.2 min. MS(m/z):[M+H]⁺=385.

Example 53

5-(S)-Azidomethyl-3-[4′-methylthio-3′-fluorophenyl]oxazolidine-2-one

5% TFA and 2.5% triisopropylsilane in DCM (4 ml) was added to5-(S)-azidomethyl-3-[4′-triphenylmethylthio-3′-fluorophenyl]oxazolidine-2-one(0.250 g, 0.490 mmol; prepared as described above for Example 6), andthe mixture stirred for 1 h at r.t. Solvent was removed under vacuum andthe residue dissolved in DMF (2 ml). Iodomethane (0.046 ml, 0.735 mmol)was added followed by dropwise addition of triethylamine (0.136 ml,0.979 mmol). The mixture was stirred at r.t. for 2 h, evaporated, andthe residue purified by PTLC (50% ethyl acetate in DCM) to give theproduct as a white solid (0.124 g, 90%). MS (m/z): [M+H]⁺=283.

5-(S)-Azidomethyl-3-[4′-methylsulfinyl-3′-fluorophenyl]oxazolidine-2-one

m-Chloroperoxybenzoic acid (77%, 0.079 g, 0.354 mmol) was addedportionwise with stirring to a solution of5-(S)-azidomethyl-3-[4′-methylthio-3′-fluorophenyl]oxazolidine-2-one(0.100 g, 0.354 mmol) in DCM (4 ml) at 0° C. The mixture was allowed towarm up to r.t. over 2 h. The mixture was washed with aq. saturatedsodium bicarbonate, brine, dried (MgSO₄), and evaporated to give productas a white solid (0.100 g, 95%). MS (m/z): [M+H]⁺=299.

5-(S)-Aminomethyl-3-[4′-methylsulfinyl-3′-fluorophenyl]oxazolidine-2-one

A mixture of triphenylphosphine (0.092 g, 0.352 mmol) and5-(S)-azidomethyl-3-[4′-methylsulfinyl-3′-fluorophenyl]oxazolidine-2-one(0.100 g, 0.335 mmol) in tetrahydrofuran (2 ml) was stirred at r.t. for4 h. Water (0.1 ml, 5.36 mmol) was added, and the mixture heated at 40°C. overnight. Solvent was evaporated under vacuum and the residuepurified by PTLC (10% methanol in DCM) to give product as a white solid(0.082 g, 86%). MS (m/z): [M+H]⁺=273.

5-(S)-Thioacetamidomethyl-3-[4′-methylsulfinyl-3′-fluorophenyl]oxazolidine-2-one

Prepared analogously to the Method A of General Methods of Preparationof 5-(S)-Thioamidomethyloxazolidinones (Example 1) from5-(S)-aminomethyl-3-[4′-methylsulfinyl-3′-fluorophenyl]oxazolidine-2-one(0.050 g, 0.184 mmol) and ethyl dithioacetate. Reaction was performed inDMF overnight. Yield 0.058 g (96%). M.p 158-60° C. MS (m/z): [M+H]+=331.

Example 54

5-(S)-Azidomethyl-3-[4′-ethylthio-3′-fluorophenyl]oxazolidine-2-one

This compound was prepared analogously to the synthesis of5-(S)-azidomethyl-3-[4′-methylthio-3′-fluorophenyl]oxazolidine-2-onefrom iodoethane (0.117 ml, 1.47 mmol) and5-(S)-azidomethyl-3-[4′-triphenylmethylthio-3′-fluorophenyl]oxazolidine-2-one(0.500 g, 0.979 mmol). Yield 0.267 g (92%). MS (m/z): [M+H]⁺=297.

5-(S)-Azidomethyl-3-[4′-ethylsulfinyl-3′-fluorophenyl]oxazolidine-2-one

This compound was prepared analogously to the synthesis of5-(S)-azidomethyl-3-[4′-methylsulfinyl-3′-fluorophenyl]oxazolidine-2-onefrom 5-(S)-azidomethyl-3-[4′-ethylthio-3′-fluorophenyl]oxazolidine-2-one(0.250 g, 0.844 mmol) and m-chloroperoxybenzoic acid (77%, 0.189 g,0.844 mmol). Yield 0.235 g (89%). MS (m/z): [M+H]⁺=313.

5-(S)-Aminomethyl-3-[4′-ethylsulfinyl-3′-fluorophenyl]oxazolidine-2-one

This compound was prepared analogously to the synthesis of5-(S)-aminomethyl-3-[4′-methylsulfinyl-3′-fluorophenyl]oxazolidine-2-onefrom5-(S)-azidomethyl-3-[4′-ethylsulfinyl-3′-fluorophenyl]oxazolidine-2-one(0.235 g, 0.752 mmol) and triphenylphosphine (0.207 g, 0.790 mmol).Yield 0.177 g (82%). MS (m/z): [M+H]⁺=287.

5-(S)-Thioacetamidomethyl-3-[4′-ethylsulfinyl-3′-fluorophenyl]oxazolidine-2-one

Prepared analogously to the Method A of General Methods of Preparationof 5-(S)-Thioamidomethyloxazolidinones (Example 1) from5-(S)-aminomethyl-3-[4′-ethylsulfinyl-3′-fluorophenyl]oxazolidine-2-one(0.0885 g, 0.309 mmol) and ethyl dithioacetate. Reaction was performedin DMF overnight. Yield 0.104 g (98%). M.p. 138-9° C. MS (m/z):[M+H]⁺=345.

Example 55

5-(S)-Azidomethyl-3-[4′-(2″-fluoroethyl)thio-3′-fluorophenyl]oxazolidine-2-one

This compound was prepared analogously to the synthesis of5-(S)-azidomethyl-3-[4′-methylthio-3′-fluorophenyl]oxazolidine-2-onefrom 1-bromo-2-fluoroethane (0.109 ml, 1.47 mmol) and5-(S)-azidomethyl-3-[4′-triphenylmethylthio-3′-fluorophenyl]-oxazolidine-2-one(0.500 g, 0.979 mmol). Yield 0.280 g (91%). MS (m/z): [M+H]⁺=315.

5-(S)-Azidomethyl-3-[4′-(2″-fluoroethyl)sulfinyl-3′-fluorophenyl]oxazolidine-2-one

This compound was prepared analogously to the synthesis of5-(S)-azidomethyl-3-[4′-methylsulfinyl-3′-fluorophenyl]oxazolidine-2-onefrom5-(S)-azidomethyl-3-[4′-(2″-fluoroethyl)thio-3′-fluorophenyl]oxazolidine-2-one(0.280 g, 0.891 mmol) and m-chloroperoxybenzoic acid (77%, 0.200 g,0.891 mmol). Yield 0.280 g (95%). MS (m/z): [M+H]⁺=331.

5-(S)-Aminomethyl-3-[4′-(2″-fluoroethyl)sulfinyl-3′-fluorophenyl]oxazolidine-2-one

This compound was prepared analogously to the synthesis of5-(S)-aminomethyl-3-[4′-methylsulfinyl-3′-fluorophenyl]oxazolidine-2-onefrom5-(S)-azidomethyl-3-[4′-(2″-fluoroethyl)sulfinyl-3′-fluorophenyl]oxazolidine-2-one(0.275 g, 0.833 mmol) and triphenylphosphine (0.229 g, 0.874 mmol).Yield 0.253 g (80%). MS (m/z): [M+H]⁺=305.

5-(S)-Thioacetamidomethyl-3-[4′-(2″-fluoroethyl)sulfinyl-3′-fluorophenyl]-oxazolidine-2-one

Prepared analogously to the Method A of General Methods of Preparationof 5-(S)-Thioamidomethyloxazolidinones (Example 1) from5-(S)-aminomethyl-3-[4′-(2″-fluoroethyl)sulfinyl-3′-fluorophenyl]oxazolidine-2-one(0.100 g, 0.329 mmol) and ethyl dithioacetate. Reaction was performed inDMF overnight. Yield 0.114 g (96%). M.p. 161° C. MS (m/z): [M+H]⁺=363.

Example 56

5-(S)-Acetamidomethyl-3-[4′-methylsulfinyl-3′-fluorophenyl]oxazolidine-2-one

Acetic anhydride (0.173 ml, 1.83 mmol) and pyridine (0.296 ml, 3.67mmol) were added to a solution of5-(S)-aminomethyl-3-[4′-methylsulfinyl-3′-fluorophenyl]oxazolidine-2-one(0.100 g, 0.367 mmol) in DCM (3 ml). The reaction mixture was stirredfor 4 h at r.t. and then evaporated to dryness under vacuum. The residuewas purified by PTLC (10% methanol in DCM) to give product as a whitesolid (0.115 g, 99%). M.p. 143-5° C. MS (m/z): [M+H]⁺=315.

5-(S)-Acetamidomethyl-3-[4′-methylsulfonyl-3′-fluorophenyl]oxazolidine-2-one

m-Chloroperoxybenzoic acid (77%, 0.0784 g, 0.350 mmol) was addedportionwise to a solution of5-(S)-Acetamidomethyl-3-[4′-methylsulfinyl-3′-fluorophenyl]oxazolidine-2-one(0.110 g, 0.350 mmol) in DCM (20 ml) at r.t. The mixture was stirred for2 h, then washed with aq. saturated sodium bicarbonate, brine, dried(MgSO₄), and evaporated to give product as a white solid (0.106 g, 92%).MS (m/z): [M+H]⁺=331.

5-(S)-Thioamidomethyl-3-[4′-methylsulfonyl-3′-fluorophenyl]oxazolidine-2-one

Prepared analogously to the Method B (Example 1) of General Methods forPreparation of 5-(S)-Thioamidomethyloxazolidinones from5-(S)-acetamidomethyl-3[4′-methylsulfonyl-3′-fluorophenyl]oxazolidinone(0.100 g, 0.303 mmol) and Lawesson's reagent. Yield 0.078 g (75%). M.p.177° C. MS (m/z): [M+H]⁺=347.

Example 57

5-(S)-Aminomethyl-3-[4′-(5″-amino-1″,3″,4″-thiadiazole-2″-yl)-3′-fluorophenyl]oxazolidine-2-one

Triphenylphosphine (0.376 g, 1.4 mmol) was added to a mixture of5-(S)-azidomethyl-3-[4′-(5″-amino-1″,3″,4″-thiadiazole-2″-yl)-3′-fluorophenyl]oxazolidine-2-one(0.402 g, 1.3 mmol; prepared as described for Example 34) in DMF (7 ml)under nitrogen atmosphere. The solution was stirred at 40° C. for 6 h,then water (0.7 ml) was added, and the reaction mixture stirred at 55°C. overnight. Most of solvent was removed under vacuum, and theresulting solid was triturated with ether. Precipitated material wasfiltered, washed with MeOH, excess of ether, and dried under vacuum toafford the product as a white solid (0.320 g, 80%). MS (m/z):[M+H]⁺=310.

5-(S)-Thioacetamidomethyl-3-[4′-(5″-amino-1″,3″,4″-thiadiazole-2″-yl)fluorophenyl]-oxazolidine-2-one

A solution of5-(S)-aminomethyl-3-[4′-(5″-amino-1″,3″,4″-thiadiazole-2″-yl)-3′-fluorophenyl]oxazolidine-2-one(0.155 g, 0.5 mmol) and ethyl dithioacetate (0.093 ml, 0.67 mmol) withtriethylamine (0.080 ml, 0.67 mmol) in DMF (2 ml) was stirred at r.t.overnight. Most of the solvent was removed under vacuum, residue washedwith ether, and the crude product purified by silica gel PTLC (eluent:10% MeOH in DCM). White crystals, yield 0.92 g (50%). HPLC R_(t)=3.8min. MS (m/z): [M+H]⁺=368.

Example 58

5-(S)-Azidomethyl-3-[4′-(thiosemicarbazide-1″-yl)carbonyl-3′-fluorophenyl]-oxazolidine-2-one

A solution of5-(S)-azidomethyl-3-[4′-carboxy-3′-fluorophenyl]oxazolidine-2-one (1.0g, 3.6 mmol; prepared as described in Example 3),O-(7-azabenzotriazol-1-yl)-N,N,N′, N′,-tetramethyluroniumhexafluorophosphate (1.5 g, 3.9 mmol) and N,N′-diisopropylethylamine(1.9 ml, 10.8 mmol) in DMF (4 ml) was stirred at r.t. for 20 minutes.Thiosemicarbazide (0.351 g, 3.9 mmol) was added, and the reactionmixture was stirred at r.t. overnight. Most of the solvent was removedunder vacuum, and the crude material purified by silica gelchromatography eluting with 20% hexanes in ethyl acetate to afford thewhite crystalline product (0.460 g, 36%). HPLC R_(t)=3.4. MS (m/z):[M+H]⁺=354.

5-(S)-Aminomethyl-3-[4′-(thiosemicarbazide-1″-yl)carbonyl-3′-fluorophenyl]-oxazolidine-2-one

Triphenylphosphine (0.376 g, 1.4 mmol) was added to a solution of5-(S)-azidomethyl-3-[4′-(thiosemicarbazide-1-yl)carbonyl-3′-fluorophenyl]-oxazolidine-2-one(0.46 g, 1.3 mmol) in THF (15 ml) under nitrogen atmosphere. Thesolution was stirred at 40° C. for 3 h, water (1.5 ml) was added, andthe reaction mixture stirred at 40° C. overnight. Solvent was removedunder vacuum, and the resulting solid was triturated with ether.Precipitated material was filtered, washed with ether and ethanol anddried under vacuum to afford the product as white crystals (0.370 g,87%). HPLC R_(t)=3.2 min. MS (m/z): [M+H]⁺=328.

5-(S)-(tert-Butoxycarbonyl)aminomethyl-3-[4′-(thiosemicarbazide-1″-yl)carbonyl-3′-fluorophenyl]-oxazolidine-2-one

di-tert-Butyl dicarbonate (0.288 g, 1.3 mmol) was added with stirring at5° C. to the mixture of5-(S)-aminomethyl-3-[4′-(thiosemicarbazide-1-yl)carbonyl-3′-fluorophenyl]-oxazolidine-2-one(0.370 g, 1.1 mmol) and triethylamine (0.31 ml, 2.2 mmol) in THF (30 ml)with DMF (5 ml). The mixture was stirred overnight at r.t., and solventwas removed under vacuum. The residue was partitioned between EtOAc andwater, and resulted emulsion filtered through Celite. Organic layer wasseparated and dried (Na₂SO₄). Evaporation of solvent afforded a whitecrystalline product (0.480 g, quant.). HPLC R_(t)=4.3 min. MS (m/z):[M+H]⁺=428.

5-(S)-(tert-Butoxycarbonyl)aminomethyl-3-[4′-(5″-amino-1″,3″,4″-oxadiazole-2″-yl)-3′-fluorophenyl]-oxazolidine-2-one

A mixture of5-(S)-(tert-butoxycarbonyl)aminomethyl-3-[4′-(thiosemicarbazide-1″-yl)carbonyl-3′-fluorophenyl]-oxazolidine-2-one(0.425 g, 1.0 mmol) and red mercury (II) oxide (0.432 g, 2.0 mmol) inDMF (3 ml) was stirred at 60° C. for 2 h. Solvent was removed undervacuum, and the crude material purified by silica gel chromatography(eluent: EtOAc) to afford a white crystalline product (0.160 g, 41%).HPLC R_(t)+4.5 min. MS (m/z): [M+H]⁺=394.

5-(S)-Thioacetamidomethyl-3-[4′-(5″-amino-1″,3″,4″-oxadiazole-2″-yl)-3′-fluorophenyl]-oxazolidine-2-one

A solution of5-(S)-(tert-butoxycarbonyl)aminomethyl-3-[4′-(5″-amino-1″,3″,4″-oxadiazole-2″-yl)fluorophenyl]-oxazolidine-2-one.(0.160 g, 0.41 mmol) in 40% trifluoroacetic acid in DCM (8 ml) wasstirred at r.t. for 1.5 h. Volatiles were removed under vacuum at r.t.,and the gummy residue redissolved in MeOH and evaporated to afford theintermediate5-(S)-aminomethyl-3-[4′-(5″-amino-1″,3″,4″-oxadiazole-2″-yl)fluorophenyl]-oxazolidine-2-onetrifluoroacetate as a white crystalline solid (HPLC R_(t)=3.1 min. MS(m/z): [M+H]⁺=294). A solution of above intermediate and ehyldithioacetate (0.093 ml, 0.67 mmol) with triethylamine (0.080 ml, 0.67mmol) in DMF (2 ml ) was stirred at r.t. for 3 h. Solvent was removedunder vacuum, and the product was purified by silica gel columnchromatography (eluted with a mixture of 1% AcOH and 15% MeOH in DCM).White crystals (0.051 g, 36%). HPLC R_(t)=4.0 min. MS (m/z): [M+H]⁺=352.

Although the foregoing invention has been described in some detail byway of illustration and example for purposes of clarity andunderstanding, it will be apparent to those skilled in the art thatcertain changes and modifications may be practical. Therefore, thedescription and examples should not be construed as limiting the scopeof the invention.

What is claimed is:
 1. A compound of Formula 4:

wherein: R₇ is aryl; R₈, is NR, S, C(═O)NR, NRC(═O), C(═O)O, OC(═O),OC(═O)NR, C(═S)NR, NRC(═S), OC(═S)NR, NRC(═S)O, or NRC(═S)NR′, wherein Rand R′ are independently H, alkyl, heteroalkyl, aryl or heteroaryl; andR₉ is hydrogen, OR″, SR″, NR″R′″, alkyl, aryl, or heteroaryl, wherein R″and R′″ each are independently H, alkyl, heteralkyl, aryl or heteroaryl;and R₁₀ and R₁₁ are independently hydrogen, alkyl, heteroalkyl, aryl orhetoroaryl, with the proviso that when R₆ is NR, C(═O)NR, or C(═O)O, andR is hydrogen or alkyl, then R₉ is different from hydrogen and alkyl;when R₈ is S, then R₉ is different from hydrogen; and, when R₉ isNRC(═O), then R₉ is different from alkyl.
 2. The compound of claim 1,wherein NR₁₀R₁₁ is NH₂, NHC₁-C₄alkyl, N(C₁-C₄alkyl)₂, or N(CH₂)₂₋₅.
 3. Acomposition for the treatment or prevention of an infectious disordercomprising an effective amount of a compound of claim 1 and apharmaceutically acceptable carrier.
 4. A method of treating orpreventing an infectious disorder in a human or other animal subject,comprising administering to the subject an effective amount of acompound of claim
 1. 5. A compound of Formula 4:

wherein: R₇ is monocyclic heteroaryl; R₆ is NR, S, C(═O)NR, NRC(═O),C(═O)O, OC(═O), OC(═O)NR, C(═S)NR, NRC(═S), OC(═S)NR, NRC(═S)O, orNRC(═S)NR′, wherein R and R′ are independently H, alkyl, heteroalkyl,aryl or heteroaryl; and R₉ is hydrogen, OR″, SR″, NR′″, alkyl, aryl, orheteroaryl, wherein R″ and R′″ each are independently H, alkyl,heteralkyl, aryl or heteroaryl; and R₁₀ and R₁₁ are independentlyhydrogen, alkyl, heteroalkyl, aryl or heteroaryl.
 6. A composition forthe treatment or prevention of an infectious disorder comprising aneffective amount of a compound of claim 5 and a pharmaceuticallyacceptable carrier.
 7. A method of treating or preventing an infectiousdisorder in a human or other animal subject, comprising administering tothe subject an effective amount of a compound of claim
 5. 8. A compoundof Formula 5:

wherein: R₇ is monocyclic heteroaryl; R₅ is NR, S, C(═O)NR, NRC(═O),C(═O)O, OC(═O), OC(═O)NR, C(═S)NR, NRC(═S), OC(═S)NR, NRC(═S)O, orNRC(═S)NR′, wherein R and R′ are independently H, alkyl, heteroalkyl,aryl or heteroaryl; and R₈ is hydrogen, OR″, SR″, NR″R′″, alkyl, aryl,or heteroaryl, wherein R″ and R′″ each are independently H, alkyl,heteroalkyl, aryl or heteroaryl; and R₁₀ is alkyl, C₁-C₄ alkyl,heteroalkyl, aryl or heteroaryl.
 9. A composition for the treatment orprevention of an infectious disorder comprising an effective amount of acompound of claim 8 and a pharmaceutically acceptable carrier.
 10. Amethod of treating or preventing an infectious disorder in a human orother animal subject, comprising administering to the subject aneffective amount of a compound of claim
 8. 11. A compound of thestructure 1b:

wherein: R₂ and R₄ are, independently, hydrogen, alkyl, heteroalkyl,heteroaryl or an electron withdrawing group, with the proviso that if R₄is hydrogen, then R₂ is different from H, F, Cl, Br, alkyl, and NO₂; R₈is aminocarbonyl or alkoxycarbonyl; and R₁ is: C(O)NR₇R₈, C(S)NR₇R₈,OC(O)NR₇R₈, OC(S)NR₇R₈, NR₇C(O)NR₇R₈, NR₇C(S)NR₇R₈, C(O)OR₇, C(O)R₇,S(O)₂R₇, or S(O)R₇, wherein R₇ and R₈ are, independently, C₅₋₁₂alkyl,heteroalkyl, aryl or heteroaryl; SR₁₂, wherein R₁₂ is hydrogen, alkyl,heteroalkyl, aryl or heteroaryl; NR₁₂R₁₄ or CH₂NR₁₃R₁₄, wherein R₁₃ ishydrogen, acyl, sulfonyl, alkyl, heteroalkyl, aryl, or heteroaryl, andR₁₄ is acyl, sulfonyl, C₅₋₁₂alkyl, heteroalkyl, aryl or heteroaryl;NR₃₀C(O)R₃₁ or NR₃₀(SO₂)R₃₁, wherein R₃₀ is hydrogen, alkyl,heteroalkyl, aryl, or heteroaryl, and R₃₁ is hydrogen, C₅₋₁₂alkyl,heteroalkyl, aryl, or heteroaryl; 2-oxazolyl comprising R₁₅ at the4-position and R₁₅ at the 5-position of the oxazolyl, wherein R₁₅ andR₁₅ are, independently, hydrogen, alkyl, heteroalkyl, aryl, heteroarylor an electron withdrawing group; 2-aminothiazolyl comprising R₁₇ at the4-position and R₁₈ at the 5-position of the thiazole, wherein R₁₇ andR₁₈, are, independently, hydrogen, alkyl, heteroalkyl, aryl, heteroarylor an electron withdrawing group; and 2-(1,3,4-thiadiazalyl) comprisingR₂₁ at the 5-position of the 1,3,4-thiadiazole, wherein R₂₁ is hydrogen,alkyl, heteroalkyl, amino(C₁₋₄alkyl), acylamino(C₁₋₄ alkyl),thioacylamino(C₁₋₄ alkyl), sulfonamido(C₁₋₄ alkyl),heterocarbonylamino(C₁₋₄ alkyl), aryl, heteroaryl, an electronwithdrawing group, or NR₂₂R₂₃, wherein R₂₂ and R₂₃ are, independently,hydrogen, acyl, thioacyl, sulfonyl, alkyl, hetoroalkyl, aryl orheteroaryl; CH═CHR₂₄ or C≡CR₂₄, wherein R₂₄ is C(O)NR₇R₈, C(S)NR₇R₈,OC(O)NR₇R₈, OC(S)NR₇R₈, NR₇C(O)NR₇R₈, NR₇C(S)NR₇R₈, C(O)OR₁₀, C(O)R₁₁,SR₁₂, S(O)₂R₁₂, S(O)R₁₂, NR₁₃R₁₄, CH₂NR₁₃R₁₄, alkyl aryl, or heteroaryl;or 5,6-dihydro-1,4,2-dioxazine-3-yl, wherein R₂₅ is at the 5-position ofdioxazine, and R₂₆ is at the 6-position of dioxazine, and wherein R₂₅and R₂₆ are, independently, hydrogen, alkyl, heteroalkyl, aryl,heteroaryl or an electron withdrawing group; wherein optionally R₁ andR₂ together are a quinolone heterocycle C(═O)C(COOH)═CHNR₂₇, or R₁ andR₈ together are a benzotriazole heterocycle NNNR₂₇, or NN(R₂₇)N, whereinR₂₇ is alkyl, aryl, or heteroaryl, with the proviso that when R₆ isalkoxycarbonyl, then R₈ is different from 2-(1,3,4-thiadiazolyl).
 12. Acomposition for the treatment or prevention of an infectious disordercomprising an effective amount of a compound of claim 11 and apharmaceutically acceptable carrier.
 13. A method of treating orpreventing an infectious disorder in a human or other animal subject,comprising administering to the subject an effective amount of acompound of claim
 11. 14. A compound of the following formula;


15. A compound of Formula 1;

wherein: R₆ is aminocarbonyl or alkoxycarbonyl; R₇ is monocyclicheteroaryl; R₈ is C₄-C₇ alkyl, C₂-C₇ alkynyl, O, OC(═O), OC(═O)NR,NRC(═O)O, C(═S)NR, NRC(═S), C(═S), C(═S)O, OC(═S), OC(═S)NR, NRC(═S)O,NRCONR′, NHC(═S)NR′, or (CH₂)_(n)O, wherein n=2-6, and wherein R and R′are independently H, alkyl heteroalkyl, aryl or heteroaryl; and R₉ ishydrogen, OH, OR″, SR″, NR″R′″, alkyl, aryl, heteroalkyl, or heteroaryl,and wherein R″ and R′″ are independently H, alkyl, heteroalkyl, aryl orheteroaryl.
 16. The compound of claim 15, wherein; R₈ is OC(═O),OC(═O)NR, C(═S)NR, NRC(═S), OC(═S)NR, NRC(═S)O, or NRC(═S)NR′, wherein Rand R′ are independently H, alkyl, heteroalkyl, aryl or heteroaryl; andR₉ is hydrogen, OR″, SR″, NR″R′″, alkyl, aryl, or heteroaryl, whereineach R″ and R′″ are independently H, alkyl, aryl or heteroaryl.
 17. Acomposition for the treatment or prevention of an infectious disordercomprising an effective amount of a compound of claim 15 and apharmaceutically acceptable carrier.
 18. A method of treating orpreventing an infectious disorder in a human or other animal subject,comprising administering to the subject an effective amount of acompound of claim 15.